Eirini Theochari

Dopamine in anorexia nervosa: a systematic review.

Anorexia nervosa (AN) is a chronic relapsing psychiatric disorder with a largely unknown pathophysiology. Dopamine has been implicated in the pathophysiology of the disorder by preclinical and clinical evidence. Preclinical studies have examined two main characteristics of AN: reduction in food intake (diet restriction) and hyperactivity. Diet restriction has been associated with reduced dopamine levels in the hypothalamus, hippocampus, and the dorsal striatum. Animal hyperactivity following diet restriction has been linked to increased dopamine in the hypothalamus. Increased dopamine in the nucleus accumbens was associated with food administration, but not food expectation. Tyrosine and dopaminergic antagonists normalized anorexia-like behaviors in animal models of AN, but did not restore body weight. Clinical studies on the etiology of AN have produced contradictory findings. Cerebrospinal fluid concentrations of dopamine and its metabolites have been reported to be decreased or normal under conditions of low weight, whereas they tended to normalize when the weight was restored. Plasma and urinary levels of dopamine and its metabolites have been found to be normal, increased, and decreased. Neuroendocrine studies suggest that dopaminergic neurotransmission is increased in AN. However, recent neuroimaging studies lend support to the increase in binding of dopaminergic receptors in the striatum, which favors the opposite theory that intrasynaptic dopamine is indeed decreased. Genetic studies implicate dopamine D2 receptors, the dopamine transporter, and the enzyme COMT. There are promising results with respect to the use of atypical antipsychotics against symptoms of AN beyond weight gain, but further trials are required.

Doubtful association of antipsychotic polypharmacy and high dosage with cognition in chronic schizophrenia

Despite consistent recommendations for antipsychotic monotherapy, antipsychotic polypharmacy (the use of two or more antipsychotic agents) and the administration of excessive doses (higher than 1000 mgr/day of chloropromazine equivalents) is a common practice in schizophrenia. The therapeutic and adverse effects of this practice are poorly studied, in particular with regards to the cognitive symptoms of the disease. In this cross-sectional study we investigated the cognitive effects of antipsychotic polypharmacy and excessive doses in 53 patients with chronic schizophrenia using non-verbal cognitive tasks involving speed of movement, memory and executive functions. No significant difference in performance scores was found between the groups under polypharmacy and monotherapy, or the groups receiving either excessive or normal doses of antipsychotics. Since these groups did not also differ in demographic, clinical, other pharmacologic parameters, in the relative anticholinergic potency of antipsychotics, or in intelligence scores, we raise doubts about the association of polypharmacy and excessive doses with non-verbal cognitive performance in chronic schizophrenia.

5-HT2C receptor involvement in the control of persistence in the Reinforced Spatial Alternation animal model of obsessive-compulsive disorder

OBJECTIVE The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD. METHODS Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence. RESULTS Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence. CONCLUSIONS These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD.

Cognitive therapy for patients with schizophrenia.

400 www.thelancet.com Vol 384 August 2, 2014 Anthony Morrison and colleagues report cognitive therapy as a safe and effective treatment alternative to antipsychotic drugs for people with schizophrenia spectrum disorders. In view of the eff ect of such a claim in The Lancet, several issues impeding the clinical translation of the study demand clarification, starting with its heterogeneous population (mixed schizophrenia and attenuated psychotic symptoms) combined with the absence of crucial clinical information (eg, psychosis duration and number of admissions). Two additional major issues question its clinical relevance. First, the authors claim that participants were moderately ill. However, baseline data (positive and negative syndrome scale [PANSS] scores below the relevant cutoff of 78 proposed by Stefan Leucht and colleagues) indicate that both groups were actually mildly ill. Consequently, the effectiveness of cognitive therapy can be attributed to the good clinical condition of participants. Second, if the methodology of Peter Lepping and colleagues, who showed that particular atypical antipsychotics produce a moderate improvement on the clinical global impression scale (CGI), is applied to Morrison and colleagues’ study, cognitive therapy produces no clinical improvement after 3 or 6 months: in the cognitive therapy group, percentage mean changes in unadjusted PANSS scores at 3 or 6 months (week 6 in Leucht and colleagues’ study) were 10·41% and 14·64%, respectively (mean CGI decrease of 0·2 and 0·5). Similarly, no clinical change was recorded in the treatment-as-usual (TAU) group at 3 or 6 months: percentage mean PANSS changes were 0·53% and 8·63%, respectively (mean CGI increase of 0·5 and 0·1). For adjusted PANSS scores, the percentage mean changes for the cognitive therapy group were 18·17% and 25·55%, (0·6 and 0·8 CGI decrease), whereas for the TAU group they were 0·9% and 14·61%, (0·4 CGI increase and 0·5 CGI decrease), respectively. Taken together, these issues challenge the usefulness of the study results for clinicians, while they might well create false expectations in patients with schizophrenia, increasing the number who would reject drug treatment.

S61. THE ASSOCIATION OF VERBAL LEARNING DEFICITS WITH AGE AND SYMPTOMS IN SCHIZOPHRENIA

Abstract Background The relationship of age and symptoms with the performance on verbal learning and memory tasks in schizophrenia could provide useful information for optimizing and individualizing the efforts to remediate the cognitive impairments of patients. Methods During a cross-sectional study, 97 medicated and stabilized patients with chronic schizophrenia (61 males and 36 females, mean age=43.74 years, standard deviation-SD=11.59), which were consecutively referred to our Unit, were assessed using the Hopkins Verbal Learning Test (HVLT) and the Positive and Negative Syndrome Scale (PANSS). A linear regression analysis was conducted in order to investigate the effect of symptoms and age on HVLT performance. Results Increased age and total PANSS symptoms were associated with worse total recall (raw scores) (B=-0.109. 95% confidence interval-C.I.- =-0.18, -0.038, t=-3.038, df=90 p=0.003 and B=-0.053, 95%CI=-0.097, -0.008, t=-2.356, df=90, p=0.021, respectively). The effect of symptoms on HVLT total recall was significant for positive (B=-0.166, 95%CI=-0.316, -0.015, t=-2.189, df=90, p=0.031), negative (B=-0.167, 95%CI=-0.279, -0.054, t=-2.949, df=90, p=0.004), but not for general psychopathology symptoms (B=-0.05, 95%CI=-0.129, 0.03, t=-1.247, df=90, p=0.216). Further analyses revealed the significant negative correlations of total symptoms with the performance in immediate recall during the first HVLT trial (B=-0.021, 95% CI=-0.036, -0.005, df=89, p=0.011), and age during the second (B=-0.046, 95%CI=-0.076,-0.017, p=0.003) and third (B=-0.048, 95%CI=-0.083, -0.014, df=89, p=0.007) HVLT immediate recall trials. Both total symptoms and age were significantly negatively correlated with the performance in recognition discrimination (raw scores) (symptoms: B=-0.199, 95%CI=-0.363, -0.035, df=87, t=-2.415, p=0.017 and age: B=-0.357, 95%CI=-0.617, -0.098, df=87, t=-2.737, p=0.008). We failed to find any significant correlation between either age or symptoms with delayed recall. Discussion Age and symptoms are associated with immediate verbal learning and memory impairments but not with deficits in verbal delayed recall in schizophrenia. The effects of medication remain to be explored in future analyses. Cognitive remediation programmes against verbal learning deficits in individuals with schizophrenia should take into account their age as well as their symptomatology.

F61. THE RELATIONSHIP OF AGE AND SYMPTOMS WITH COGNITIVE PLANNING IN SCHIZOPHRENIA

Abstract Background The relationship of age and symptoms with the performance on non-verbal cognitive planning tasks in schizophrenia could be useful for the development of cognitive remediation programmes. Methods During a cross-sectional study, 97 medicated and stabilized patients with chronic schizophrenia (61 males and 36 females, mean age=43.74 years, standard deviation-SD=11.59), which were consecutively referred to our Unit, were assessed using the Stockings of Cambridge (SOC) task of the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the Positive and Negative Syndrome Scale (PANSS). Linear regression analyses were conducted in order to investigate the correlations of symptoms and age with SOC performance. Results Age and PANSS total scores negatively correlated with optimal SOC solutions (problems solved in minimum moves) (age: B=-0.05, 95% CI=-0.089, -0–012, df=86, t=-2.599, p=0.011, symptoms: B=-0.047, 95%CI=-0.071, -0.024, df=86, t=-3.982, p<0.001). The effects of total symptoms were driven by positive (B=-0.149, 95%CI=-0.229, -0.068, df=86 t=-3.672, p<0.001), negative (B=-0.087, 95%CI=-0.150, -0.023, df=86, t=-2.717, p=0.008) and general psychopathology symptoms (B=-0.065, 95%CI=-0.108, -0.023, df=86, t=-3.045, p=0.03). PANSS total scores positively correlated with mean excess moves in 2- (B=0.007, 95%CI=0.002, 0.012, df=86, t=2.656, p=0.009), 3- (B=0.014, 95%CI=0.005, 0.023, df=86, t=2.951, p=0.004) and 5-move (B=0.026, 95%CI=0.008, 0.044, df=86, t=2.923, p=0.004) problems and age only in 4- (B=0.026, 95%CI=0.006, 0.046, df=86, t=2.571, p=0.012) and 5-move (B=0.032, 95%CI=0.002, 0.061, df=86, t=2.152, p=0.034) problems. We could not find any association between PANSS scores and age with initial or subsequent thinking times during the SOC task. Discussion Cognitive planning deficits in schizophrenia are associated with patients’ symptoms and age. Whereas the effect of symptoms appears to be independent of task difficulty, the age effect emerges when the planning tasks become more complex. The role of drugs remains to be examined in future analyses.

Preclinical and Clinical Investigation of Antipsychotic Polypharmacy: What Is the Evidence?

Antipsychotic polypharmacy is a common clinical practice whose implications have not been thoroughly assessed to date. There is a paucity of preclinical studies investigating the effects of antipsychotic combinations on animal models. These models are focusing on the effects of antipsychotic combinations on psychiatric and extrapyramidal symptoms’ simulations and on antipsychotic-induced metabolic abnormalities. Although most guidelines favour the use of antipsychotic monotherapy, clinical trials and meta-analyses examining the merits and disadvantages of polypharmacy are contradictory. A recent synthetic approach suggests that antipsychotic polypharmacy could be useful under conditions of acute symptoms’ exacerbation non-responsive to monotherapy but not so beneficial in chronic refractory illness. It also recommends that antipsychotic polypharmacy should always have a rational pharmacological basis. The role of antipsychotic combination strategies other than clozapine augmentation in treatment resistant patients needs to be clarified in future research. The specific effects of antipsychotic co-treatment in different symptoms dimensions, its interactions, adverse reactions and associations with medical morbidity and mortality remain to be further examined through rigorously designed clinical trials and prospective epidemiological studies.

P03-78 - No effects of polypharmacy and antipsychotic dose on spatial working memory in schizophrenia

Objectives Antipsychotic polypharmacy and high doses have been associated with poor outcome and increased adverse effects in schizophrenia. However, their relation to cognition has been poorly studied. Methods 40 right-handed patients (mean age: 42.87 years; SD:10.57) with DSM-IV schizophrenia, were recruited in an acute psychiatric ward. They were assessed on the Spatial Working Memory test (SWM) of the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the Wechsler Adult Intelligence Scale (WAIS-III) at a time when they were able to cooperate with neuropsychological testing. The pattern of their pharmacological treatment was also assessed. Statistical correlation and Mann-Whitney tests were performed using the SPSS, as appropriate. Results 18 patients were receiving antipsychotic polypharmacy (≥2 antipsychotics) and 22 monotherapy. 13 patients received an excessive (≥1000 chloropromazine mEq(CmEq)/day), and 22 a normal antipsychotic dosage. No significant difference was detected on any of the SWM performance measures between the two groups of patients receiving either polypharmacy or monotherapy. These groups did not also differ in the WAIS full scale, performance or verbal IQ scores. When the patients were divided into two groups receiving either an excessive or a normal dose of antipsychotics, these two groups also showed a similar SWM and WAIS performance. The total antipsychotic dose showed negative but nonsignificant correlations with the SWM performance scores. Conclusions We did not detect any influence of antipsychotic polypharmacy or excessive dosing on spatial working memory in schizophrenia. This finding supports the independence of working memory deficits from the effects of treatment in schizophrenia.

The effect of psychopathology on set shifting and reversal learning in schizophrenia

The effect of psychopathology on set shifting and reversal learning in schizophrenia Eirini Theochari, Dimitrios Kontis, Spiros Kleisas, Stamatina Kalogerakou, Angeliki Andreopoulou, Charalambos Karouzos, Eleftheria Tsaltas From 1 International Congress on Neurobiology and Clinical Psychopharmacology and European Psychiatric Association Conference on Treatment Guidance Thessaloniki, Greece. 19-22 November 2009

Relationship of parental age with set shifting and reversal learning in schizophrenia

Relationship of parental age with set shifting and reversal learning in schizophrenia Dimitrios Kontis, Spiros Kleisas, Eirini Theochari, Stamatina Kalogerakou, Angeliki Andreopoulou, Rafail Psaras, Charalambos Karouzos, Eleftheria Tsaltas From 1 International Congress on Neurobiology and Clinical Psychopharmacology and European Psychiatric Association Conference on Treatment Guidance Thessaloniki, Greece. 19-22 November 2009