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P.3.14 Early subjective response to antipsychotics: relationship with cognition and treatment adherence in adolescent psychosis
S80
Clinical neuropsychopharmacology
identified in the transcriptional control region upstream of the 14 exons of the 5-HTT coding sequence. The deletion was associated with reduced transcriptional efficiency and decreased expression of 5-HTT protein both in vitro and in vivo. The serotonin promoter is a target for many antidepressant drugs, and the main target of selective serotonin reuptake inhibitors (SSRIs). In depressed patients 5-HTTLPR genotype biased the antidepressant response to SSRIs, with l/l (long/long) subjects showing the best effects and s/s (short/short) subjects the worse. Our group showed that the 5-HTTLPR genotype is able to bias in the same direction the antidepressant response to chronotherapeutic techniques such as Total Sleep Deprivation (TSD) and light therapy in bipolar depression (Benedetti et al., 1999a). Animal studies indicated that lithium treatment enhances brain serotoninergic activitity, facilitates the neural uptake of tryptophan and the release of serotonin from the nerve terminals. Moreover it has been proposed that lithium incerases the number of 5-HT transporters in frontal, temporal and cingulate cortex. Studies in humans generally suggest that lithium has a net enhancing effect on 5-HT function. Moreover our group showed that ongoing lithium treatment enhances the acute effect of TSD and prevents short-term relapses (Benedetti et al., 1999b). Following this perspective it could be hypothesized a possible interaction between lithium ongoing treatment and 5-HTTLPR gene polymorphism in influencing the antidepressant response to TSD. Aim: To investigate the possible interaction between lithium salts and 5-HTTLPR gene polymorphism in influencing the antidepressant response to TSD in bipolar depressed patients. Method: We studied 161 (F = 110, M = 51) consecutively admitted inpatients affected by Bipolar Disorder, current depressive episode without psychotic features. All patients were administered one TSD night. 47 patients were on ongoing chronic lithium medication. Perceived mood levels were assessed by a selfadministered visual analogue scale (VAS) the day before and the day after the TSD night. Genotyping of 5-HTTLPR was performed for each patients. Results: No difference in demographic characteristics was found beetwen lithium treated and lithium free patients. Lithium takers showed a shorter duration of the current depressive episode (t = −2.59, p = 0.01) but no other clinical difference was found beetwen the two groups. A three-way repeated measures ANOVA with changes in VAS scores as dependent variable and with time, lithium and genotype as independent factors showed a time x lithium x genotype significative interaction (F = 3.62;
p = 0.028). Covariation for the current depressive episode duration did not influence the analysis significance. Conclusions: Lithium therapy reversed 5-HTTLPR gene polymorphism influence on antidepressive response to TSD, causing a better response in s allele homozygotes. Preclinical studies showed that chronic lithium administration caused an increase in the number of 5-HT transporters in rat cerebral cortex and reduced the functionality of 5-HT1A receptors (Carli et al., 1977). Both these two effects could counteract the mechanism by which 5-HTTLPR hampers clinical response to antidepressant. Reference(s) [1] Benedetti F, Serretti A, Colombo C, et al., 1999a, Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of Total Sleep Deprivation in bipolar depression. Am J Psychiatr 156, 1450–1452. [2] Benedetti F, Colombo C, Barbini B, et al., 1999b, Ongoing lithium treatment prevents relapse after total sleep deprivation. J Clin Psychopharmacol 19, 240– 245. [3] Carli M, Reader TA, 1997. Regulation of central serotonin transporters by chronic lithium. Synapse 27, 83−89. P.3.14 Early subjective response to antipsychotics: relationship with cognition and treatment adherence in adolescent psychosis A. Zabala, D. Fraguas, O. Robles, M. Parellada, M.D. Moreno, M.T. Burdalo, M. Mayoral, C. Arango. Hospital General Universitario Gregorio Mara˜no´ n, Unidad Adolescentes, Madrid, Spain Introduction: Initial patient attitude toward treatment is an important factor for medication adherence, which is a crucial factor for outcome in psychosis (1). Cognitive deficits are considered an inherent feature of psychosis and have been related to the patient’s ability to manage with the antipsychotic medication prescribed in this population (2). Objectives: To investigate the relationship between early subjective response to antipsychotic treatment and cognitive functioning in adolescents with first episode psychosis and to determine the predictive value of early attitude to medication for treatment adherence. Methods: Participants included 41 adolescents with a first episode psychosis who participated in a 6-month, open, comparative (quetiapine versus olanzapine), randomised pilot study. Patients were consecutively admitted
Clinical neuropsychopharmacology to an adolescent psychiatric unit of a general hospital in Madrid, Spain. Diagnostic information was collected at baseline by using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL). Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The initial attitude of patients toward medication was evaluated using the Drug Attitude Inventory (DAI-10). The adherence to treatment was measured whether or not the patient completed the clinical trial. A thorough neuropsychological battery measuring the following domains was administered at baseline: attention and concentration (TMT-A, digit forward, Stroop interference), working memory (digit backwards, letter number sequencing), executive functioning (Wisconsin card sorting test, TMT B-A/A, verbal fluency) and memory (the Spanish adaptation of the California verbal learning test). Normative data for cognitive individual tests were obtained from a paired healthy control group. At the basal DAI assessment, prior to randomisation, all patients were stabilized on risperidone 2 to 6 mg. Results: The mean age of patients was 15.90±1.90 (range 12−18). Patients who completed the 6-month clinical trial (66%) obtained significantly higher scores on the basal DAI scale than patients who interrupted treatment or dropped out of the study (34%) (U = 111.5, p = 0.032). The likelihood of becoming medication nonadherent in 6 months was greater in subjects whose basal DAI score was lower (OR = 1.59, 95% CI: 1.052, 2.411, p = 0.028), whereas other factors such as gender, assigned antipsychotic treatment, or basal symptomatology did not predict medication adherence. Cognitive deficits were detected in all the domains evaluated. Poorer performance in cognitive tasks that assessed attention and concentration were associated with a poorer basal DAI score (r = 0.77, p = 0.016). This result was obtained in a partial correlation controlling for socio-demographic and clinical variables. Discussion: These results suggest that initial subjective experience with antipsychotic medication in adolescents with psychosis may determine future adherence to treatment, and that this early response is related to cognitive deficits. Future interventions may consider the patient’s beliefs and subjective feelings about medication an important target and may focus on improving specific cognitive deficits in order to improve long-term adherence in the treatment of adolescents with a first psychotic episode. Reference(s) [1] Perkins DO, Johnson JL, Hamer RM, et al., 2006, Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode. Schizophrenia Research 83(1): 53−63.
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[2] Kim SW, Shin IS, Kim JM, et al., 2006, Association between attitude toward medication and neurocognitive function in schizophrenia. Clinical Neuropharmacology 29(4): 197–205.
P.3.15 Repeated electrostimulation of rewardrelated brain regions alters cocaine but not ‘natural’ reward associated behaviors D. Levy1 , M. Shabt-Simon1 , N. Barnea-Ygael2 , A. Katzir1 , A. Zangen1 . 1 Weizmann Institute of Science, neurobiology, Rehovot, Israel; 2 Bar-Ilan University, Multidisciplinary Brain Research Center, Ramat-Gan, Israel Purpose: The aim of this study was to examine the effect of repeated intracranial electrical stimulation of rewardrelated regions on cocaine and sucrose (serving as a natural reward) associated behaviors. Methods: We investigated the influence of experimenterdelivered ICES treatment (10 days, 30 minutes/day, 100 Hz; 0.1 ms pulse duration; 100–800 mA intensity) of the medial forebrain bundle at the level of the lateral hypothalamus (LH) or the prefrontal cortex (PFC) on cocaine or sucrose seeking behavior and craving, measured by the cocaine self-administration paradigm (0.5 ml/kg/infusion), and by the expression of psychomotor sensitization in rats previously exposed to daily cocaine (15 mg/kg/day for 7 days, i.p.). In addition, we examined the effect of ICES on the levels of glutamate receptor subtypes (NMDAR1 and GluR1) in subregions of the ventral tegmental area (VTA) and the nucleus accumbens (NAc) using immunonhistochemistry. Results: In rats trained for cocaine but not sucrose selfadministration, ICES of either the LH (T-test, P < 0.05) or the PFC (P < 0.05) significantly reduced cocaine seeking behavior compared to sham-stimulated rats, as measured by the rate of active lever responses in a drug free test. A day later, rats were tested under a progressive ratio schedule of reinforcement. In rats trained for cocaine but not sucrose self-administration, ICES of the PFC (T-test, P < 0.05) but not the LH (P > 0.05) significantly reduced the number of active lever responses compared to shamstimulated rats (the “break point”). In another group of rats we tested the effect of ICES treatment on the expression of psychomotor sensitization. Repeated ANOVA for the LH and PFC rats revealed a significant group (F3,26 = 6, p < 0.005; F3,27 = 4.95, p < 0.01) and time (F3,11 = 35.7, p < 0.0001; F3,11 = 17.8, p < 0.0001) effects, respectively. Post-hoc analysis revealed that in the LH cocaine-pretreated rats, the distance traveled by stimulated rats (n = 8) was
Clinical neuropsychopharmacology
identified in the transcriptional control region upstream of the 14 exons of the 5-HTT coding sequence. The deletion was associated with reduced transcriptional efficiency and decreased expression of 5-HTT protein both in vitro and in vivo. The serotonin promoter is a target for many antidepressant drugs, and the main target of selective serotonin reuptake inhibitors (SSRIs). In depressed patients 5-HTTLPR genotype biased the antidepressant response to SSRIs, with l/l (long/long) subjects showing the best effects and s/s (short/short) subjects the worse. Our group showed that the 5-HTTLPR genotype is able to bias in the same direction the antidepressant response to chronotherapeutic techniques such as Total Sleep Deprivation (TSD) and light therapy in bipolar depression (Benedetti et al., 1999a). Animal studies indicated that lithium treatment enhances brain serotoninergic activitity, facilitates the neural uptake of tryptophan and the release of serotonin from the nerve terminals. Moreover it has been proposed that lithium incerases the number of 5-HT transporters in frontal, temporal and cingulate cortex. Studies in humans generally suggest that lithium has a net enhancing effect on 5-HT function. Moreover our group showed that ongoing lithium treatment enhances the acute effect of TSD and prevents short-term relapses (Benedetti et al., 1999b). Following this perspective it could be hypothesized a possible interaction between lithium ongoing treatment and 5-HTTLPR gene polymorphism in influencing the antidepressant response to TSD. Aim: To investigate the possible interaction between lithium salts and 5-HTTLPR gene polymorphism in influencing the antidepressant response to TSD in bipolar depressed patients. Method: We studied 161 (F = 110, M = 51) consecutively admitted inpatients affected by Bipolar Disorder, current depressive episode without psychotic features. All patients were administered one TSD night. 47 patients were on ongoing chronic lithium medication. Perceived mood levels were assessed by a selfadministered visual analogue scale (VAS) the day before and the day after the TSD night. Genotyping of 5-HTTLPR was performed for each patients. Results: No difference in demographic characteristics was found beetwen lithium treated and lithium free patients. Lithium takers showed a shorter duration of the current depressive episode (t = −2.59, p = 0.01) but no other clinical difference was found beetwen the two groups. A three-way repeated measures ANOVA with changes in VAS scores as dependent variable and with time, lithium and genotype as independent factors showed a time x lithium x genotype significative interaction (F = 3.62;
p = 0.028). Covariation for the current depressive episode duration did not influence the analysis significance. Conclusions: Lithium therapy reversed 5-HTTLPR gene polymorphism influence on antidepressive response to TSD, causing a better response in s allele homozygotes. Preclinical studies showed that chronic lithium administration caused an increase in the number of 5-HT transporters in rat cerebral cortex and reduced the functionality of 5-HT1A receptors (Carli et al., 1977). Both these two effects could counteract the mechanism by which 5-HTTLPR hampers clinical response to antidepressant. Reference(s) [1] Benedetti F, Serretti A, Colombo C, et al., 1999a, Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of Total Sleep Deprivation in bipolar depression. Am J Psychiatr 156, 1450–1452. [2] Benedetti F, Colombo C, Barbini B, et al., 1999b, Ongoing lithium treatment prevents relapse after total sleep deprivation. J Clin Psychopharmacol 19, 240– 245. [3] Carli M, Reader TA, 1997. Regulation of central serotonin transporters by chronic lithium. Synapse 27, 83−89. P.3.14 Early subjective response to antipsychotics: relationship with cognition and treatment adherence in adolescent psychosis A. Zabala, D. Fraguas, O. Robles, M. Parellada, M.D. Moreno, M.T. Burdalo, M. Mayoral, C. Arango. Hospital General Universitario Gregorio Mara˜no´ n, Unidad Adolescentes, Madrid, Spain Introduction: Initial patient attitude toward treatment is an important factor for medication adherence, which is a crucial factor for outcome in psychosis (1). Cognitive deficits are considered an inherent feature of psychosis and have been related to the patient’s ability to manage with the antipsychotic medication prescribed in this population (2). Objectives: To investigate the relationship between early subjective response to antipsychotic treatment and cognitive functioning in adolescents with first episode psychosis and to determine the predictive value of early attitude to medication for treatment adherence. Methods: Participants included 41 adolescents with a first episode psychosis who participated in a 6-month, open, comparative (quetiapine versus olanzapine), randomised pilot study. Patients were consecutively admitted
Clinical neuropsychopharmacology to an adolescent psychiatric unit of a general hospital in Madrid, Spain. Diagnostic information was collected at baseline by using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL). Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The initial attitude of patients toward medication was evaluated using the Drug Attitude Inventory (DAI-10). The adherence to treatment was measured whether or not the patient completed the clinical trial. A thorough neuropsychological battery measuring the following domains was administered at baseline: attention and concentration (TMT-A, digit forward, Stroop interference), working memory (digit backwards, letter number sequencing), executive functioning (Wisconsin card sorting test, TMT B-A/A, verbal fluency) and memory (the Spanish adaptation of the California verbal learning test). Normative data for cognitive individual tests were obtained from a paired healthy control group. At the basal DAI assessment, prior to randomisation, all patients were stabilized on risperidone 2 to 6 mg. Results: The mean age of patients was 15.90±1.90 (range 12−18). Patients who completed the 6-month clinical trial (66%) obtained significantly higher scores on the basal DAI scale than patients who interrupted treatment or dropped out of the study (34%) (U = 111.5, p = 0.032). The likelihood of becoming medication nonadherent in 6 months was greater in subjects whose basal DAI score was lower (OR = 1.59, 95% CI: 1.052, 2.411, p = 0.028), whereas other factors such as gender, assigned antipsychotic treatment, or basal symptomatology did not predict medication adherence. Cognitive deficits were detected in all the domains evaluated. Poorer performance in cognitive tasks that assessed attention and concentration were associated with a poorer basal DAI score (r = 0.77, p = 0.016). This result was obtained in a partial correlation controlling for socio-demographic and clinical variables. Discussion: These results suggest that initial subjective experience with antipsychotic medication in adolescents with psychosis may determine future adherence to treatment, and that this early response is related to cognitive deficits. Future interventions may consider the patient’s beliefs and subjective feelings about medication an important target and may focus on improving specific cognitive deficits in order to improve long-term adherence in the treatment of adolescents with a first psychotic episode. Reference(s) [1] Perkins DO, Johnson JL, Hamer RM, et al., 2006, Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode. Schizophrenia Research 83(1): 53−63.
S81
[2] Kim SW, Shin IS, Kim JM, et al., 2006, Association between attitude toward medication and neurocognitive function in schizophrenia. Clinical Neuropharmacology 29(4): 197–205.
P.3.15 Repeated electrostimulation of rewardrelated brain regions alters cocaine but not ‘natural’ reward associated behaviors D. Levy1 , M. Shabt-Simon1 , N. Barnea-Ygael2 , A. Katzir1 , A. Zangen1 . 1 Weizmann Institute of Science, neurobiology, Rehovot, Israel; 2 Bar-Ilan University, Multidisciplinary Brain Research Center, Ramat-Gan, Israel Purpose: The aim of this study was to examine the effect of repeated intracranial electrical stimulation of rewardrelated regions on cocaine and sucrose (serving as a natural reward) associated behaviors. Methods: We investigated the influence of experimenterdelivered ICES treatment (10 days, 30 minutes/day, 100 Hz; 0.1 ms pulse duration; 100–800 mA intensity) of the medial forebrain bundle at the level of the lateral hypothalamus (LH) or the prefrontal cortex (PFC) on cocaine or sucrose seeking behavior and craving, measured by the cocaine self-administration paradigm (0.5 ml/kg/infusion), and by the expression of psychomotor sensitization in rats previously exposed to daily cocaine (15 mg/kg/day for 7 days, i.p.). In addition, we examined the effect of ICES on the levels of glutamate receptor subtypes (NMDAR1 and GluR1) in subregions of the ventral tegmental area (VTA) and the nucleus accumbens (NAc) using immunonhistochemistry. Results: In rats trained for cocaine but not sucrose selfadministration, ICES of either the LH (T-test, P < 0.05) or the PFC (P < 0.05) significantly reduced cocaine seeking behavior compared to sham-stimulated rats, as measured by the rate of active lever responses in a drug free test. A day later, rats were tested under a progressive ratio schedule of reinforcement. In rats trained for cocaine but not sucrose self-administration, ICES of the PFC (T-test, P < 0.05) but not the LH (P > 0.05) significantly reduced the number of active lever responses compared to shamstimulated rats (the “break point”). In another group of rats we tested the effect of ICES treatment on the expression of psychomotor sensitization. Repeated ANOVA for the LH and PFC rats revealed a significant group (F3,26 = 6, p < 0.005; F3,27 = 4.95, p < 0.01) and time (F3,11 = 35.7, p < 0.0001; F3,11 = 17.8, p < 0.0001) effects, respectively. Post-hoc analysis revealed that in the LH cocaine-pretreated rats, the distance traveled by stimulated rats (n = 8) was