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S.17.04 Side effects of antipsychotic polypharmacy
S.17 Antipsychotic polypharmacy for the treatment of schizophrenia S.17.02 Clozapine augmentation with another antipsychotic for treatment-resistant schizophrenia: a meta-analysis T.R.E. Barnes1 ° , C. Whittington2 , C. Paton1 . 1 Imperial College, Department of Psychological Medicine, London, United Kingdom; 2 University College, Centre for Outcomes Research and Effectiveness, London, United Kingdom In around a third of people with treatment-resistant schizophrenia, the illness shows a poor or only partial response to an adequate trial of clozapine monotherapy (Barnes et al 2003). In such cases, augmentation with either a first or second generation antipsychotic is a relatively common strategy in clinical practice. However, the research evidence to justify this is limited, and the results from recent clinical trials are equivocal. We conducted a systematic literature search and identified four, eligible, placebo-controlled RCTs, with a total of 166 participants, for a meta-analysis (Paton et al 2007). With criterion change in BPRS/PANSS total score as the main outcome measure, considering the four studies together did not show any advantage for active drug over placebo. However, pooling effect sizes across the studies revealed clinically important heterogeneity. Analysing by the augmenting antipsychotic used (risperidone in three of the studies, sulpiride in the other) did not account for the heterogeneity, whereas analysing by the duration of the study did: examining just the two RCTs that lasted for 10 weeks or more revealed a medium effect size. In eight open studies of clozapine augmentation with a second antipsychotic, a similar relationship between response and duration of treatment may be detected. The main treatment-emergent side effects reported with augmentation were extrapyramidal side effects and raised serum prolactin. A tentative conclusion is that an adequate individual clinical trial of clozapine augmentation with another antipsychotic drug for a treatment-resistant schizophrenic illness may need to be longer than the 4−6 weeks usually recommended for acute antipsychotic monotherapy. References [1] Barnes TRE, Buckley P, Schulz SC, 2003, Treatment-resistant schizophrenia. In: Hirsch SR, Weinberger DR (editors), Schizophrenia, 2nd edition. Oxford: Blackwell Publishing, pp. 489–516. [2] Paton C, Whittington C, Barnes TRE, 2007, Augmentation with a second antipsychotic in patients with schizophrenia who partially respond to clozapine: a meta-analysis. J Clin Psychopharmacol 27, 198–204.
S.17.03 An epidemiological and long-term outcome perceptive on antipsychotic polypharmacy J.L. Waddington1 ° , D.J. Browne2 , P.J. Scully2 . 1 Royal College of Surgeons in Ireland, Molecular and Cellular Therapeutics, Dublin 2, Ireland; 2 St. Davnet’s Hospital, Stanley Research Unit, Monaghan, Ireland Though polypharmacy remains widespread in the treatment of psychotic illness, evidence for its effectiveness remains largely anecdotal. Additionally, whether polypharmacy (dis)improves the risk-benefit ratio relative to monotherapy has received little systematic attention. Polypharmacy, for example with two or more antipsychotics, might usefully combine diverse pharmacological actions or deliver drug actions at lower overall doses than would be the case for a single agent; it might also combine disadvantageous actions or result in interactions associated with acute or chronic adverse effects. We have been studying the well established and
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distressing increase in mortality associated with psychotic illness; even when risk for suicide is controlled for, patients with psychotic illness are at up to 2-fold increase for death over long-term follow-up. In an initial study of a long-term inpatient population, the maximum number of antipsychotics given concurrently over previous treatment history was associated with reduced survival over the following 10 years. In a subsequent study of a younger, mainly outpatient population, the number of antipsychotics given concurrently at index evaluation did not predict reduced survival over the following 7 years; however, the nature of outpatient care made it difficult to document lifetime medication histories. In our current study, also in a mainly outpatient population, treatment with an antidepressant in addition to a mood stabilizer for bipolar disorder was associated with reduced survival over the following 7 years. Polypharmacy is a complex challenge that requires further systematic study. References [1] Waddington JL, Youssef HA, Kinsella A, 1998, Mortality in schizophrenia in relation to antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry 173, 325–329.
S.17.04 Side effects of antipsychotic polypharmacy F. Drago ° , F. Caraci. University of Catania, Dept. of Experimental and Clinical Pharmacology, Catania, Italy Antipsychotic polypharmacy refers to the use of two or more antipsychotics concurrently in a single patient. The prevalence of antipsychotic polypharmacy has greatly increased, particularly since the advent of the second generation antipsychotics [1]. Treatment resistance, reduction of dose-related side effects caused by antipsychotic monotherapy or the effect on concomitant symptoms of schizophrenia, such as comorbid depression, might justify combination therapy or augmentation strategies. However, antipsychotics are frequently co-prescribed as long-term therapy, a use with little rationale or evidence. Data from literature such as RCTs, naturalistic cohort studies and numerous case reports provide scarce evidence of antipsychotic polypharmacy efficacy [2]. Thus, antipsychotic polypharmacy should not be granted in the management of chronic schizophrenia. Exception can be represented by the association of two antipsychotics, of which one will be shortly replaced by a newly prescribed drug in a therapy switch schedule. Antipsychotic polypharmacy is frequently associated with reduced patient compliance and increased risk of undesired side effects [2]. The complication of the clinical picture is due to the superimposition of different mechanisms of action, i.e. the anticholinergic, the antihistaminergic and the antinoradrenergic mechanisms of antipsychotics [3]. Studies which examined the side effect burden in schizophrenic patients treated with antipsychotic polypharmacy showed higher rates of anticholinergic and extrapyramidal side effects of antipsychotic polypharmacy compared to monotherapy [3]. Antipsychotic polypharmacy has been also implicated in reduced survival, possibly secondary to cardiotoxic effects of antipsychotic medication. Antipsychotic polypharmacy can also increase the potential for negative drug interactions. Side effects associated with combination therapy may themselves require treatment with additional drugs, further complicating the patient’s pharmacological regimen and potentially reducing his compliance.
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S.18 Cannabis use in adolescents: effects on brain and behaviour
References [1] Barbui C, Nose M, Mazzi MA, Thornicroft G, Schene A, Becker T, Bindman J, Leese M, Helm H, Koeter M, Weinmann S, Tansella M, 2006, Persistence with polypharmacy and excessive dosing in patients with schizophrenia treated in four European countries. Int Clin Psychopharmacol 21, 355–362. [2] Gardos G, 2005, Antipsychotic polypharmacy or monotherapy? Neuropsychopharmacol Hung 7, 72−77. [3] Stahl SM, Grady MM, 2004, A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation. Curr Med Chem 11, 313–327.
S.17.05 Combination treatments beyond antipsychotic polypharmacy P. Falkai ° , T. Wobrock. University of G¨ottingen, Department of Psychiatry and Psychotherapy, G¨ottingen, Germany Although international guidelines on schizophrenia indicate that monotherapy with antipsychotics should be preferred, in clinical practice most patients receive two and more antipsychotics. There are only few evidence-based recommendations for a targeted combination, primarily based on a theoretical rationale: – Low and high D2-binding: Agents like clozapine demonstrate a relatively low D2-blockade. One way to increase therapeutic efficacy could be to increase D2-blockade by adding substances like haloperidol or risperidone. Concerning the augmentation with risperidone there are some open-label studies and one double-blind controlled study supporting the benefit of this combination but one large scale double-blind study does not. – Loose- and tight-binder: Antipsychotics can be classified whether they bind to the D2-receptor for a longer (e.g. haloperidol, risperidone as tight-binder) or shorter period of time (e.g. quetiapine as a substance with a loose-binding potential). Although this is an interesting concept it is recently questioned whether it can be helpful for combining neuroleptics. – D2-/5HT2- and only D2-modulating neuroleptics: In accordance with the combination of antidepressants one rational could be to combine different modes of actions. There is some evidence from open-label studies that the combination of for instance clozapine with amisulpride is beneficial. In summary, there are theoretical assumptions for a rational combination of neuroleptics in the treatment of schizophrenia. Actually warranted are treatment pathways for schizophrenia in order to reduce the number of treatment resistant patients. Combining neuroleptics is one aspect, but the combination with antidepressants, benzodiazepines and mood stabilizers may be in some respect even more important.
S.18 Cannabis use in adolescents: effects on brain and behaviour S.18.01 Psychoneuroendocrine effects of cannabinoids in critical developmental periods M.P. Viveros ° . Universidad Complutense Facultad de Biolog´ıa, Departamento de Fisiolog´ıa (Fisiolog´ıa Animal II), Madrid, Spain The periadolescent period represents a critical phase in development characterized by increased neurobehavioural plasticity and specific behavioural features, such as enhanced impulsivity and novelty/sensation seeking. During this period, major neuroendocrine changes are taking place and important neural structures and pathways are still developing. Moreover, there appears to be a unique vulnerability to psychological disorders and to the negative effects of psychoactive drugs. Cannabis is one of the most abused drugs among adolescents. Its main psychoactive component, delta 9 tetrahidrocannabinol (delta-9-THC), exerts its effects by activating the cannabinoid CB1 receptors which are densely expressed in brain areas involved in the regulation of emotional responses and brain reward. The endocannabinoid system appears to play a major functional role in maintaining homeostasis, notably as regards modulation of neuroendocrine responses to stress. Thus, challenge of the system by the use of cannabis during a critical developmental period such as adolescence is likely to result in particularly disrupted neuroendocrine function and inadequate emotional responses. In fact, there is strong support for a link between cannabis and the development and exacerbation of psychosis and other neuropsychiatric disorders. Clear associations have been found between cannabis use and the use of other illicit drugs. Experimental studies may contribute to assess whether cannabis might act as a gateway drug. There are intriguing sexual dimorphisms as regards cannabis effects that might influence the pattern and motivations of its consumption. Further systematic investigation of gender differences may help in the establishment of adequate prevention and therapeutical strategies. References [1] Marco EM, Granstrem O, Moreno E, Llorente R, Adriani W, Laviola G, Viveros MP, 2007, Subchronic nicotine exposure in adolescence induces long-term effects on hippocampal and striatal cannabinoid-CB1 and mu-opioid receptors in rats. Eur J Pharmacol 557, 37−43. [2] Viveros MP, Llorente R, Moreno E, Marco EM, 2005, Behavioural and neuroendocrine effects of cannabinoids in critical developmental periods. Behav Pharmacol 16, 353−62. [3] Viveros MP, Marco EM, File SE, 2006, Nicotine and cannabinoids: parallels, contrasts and interactions. Neurosci Biobehav Rev 30, 1161−81.
References [1] Falkai P, Wobrock T Lieberman J, Glenthoj B, Gattaz WF, Moller HJ; WFSBP Task Force on Treatment Guidelines for Schizophrenia, 2005, World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, Part 1: acute treatment of schizophrenia. World J Biol Psychiatry 6, 132–191. Review.
S.18.02 Cannabis effects on brain function and structure of adolescents and young adults R.I. Block1 ° , D.S. O’Leary2 , G. Jager3 , J.M. Zuccarelli1 , M.M. Becker1 , M. Luijten3 , N.F. Ramsey3 . 1 University of Iowa, Department of Anesthesia, Iowa City, USA; 2 University of Iowa, Department of Psychiatry, Iowa City, USA; 3 University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience Department of Neurosurgery, Utrecht, The Netherlands We are conducting a United States – Netherlands collaborative functional magnetic resonance imaging (MRI) research study to examine the effects of chronic cannabis use on brain function
S.17.03 An epidemiological and long-term outcome perceptive on antipsychotic polypharmacy J.L. Waddington1 ° , D.J. Browne2 , P.J. Scully2 . 1 Royal College of Surgeons in Ireland, Molecular and Cellular Therapeutics, Dublin 2, Ireland; 2 St. Davnet’s Hospital, Stanley Research Unit, Monaghan, Ireland Though polypharmacy remains widespread in the treatment of psychotic illness, evidence for its effectiveness remains largely anecdotal. Additionally, whether polypharmacy (dis)improves the risk-benefit ratio relative to monotherapy has received little systematic attention. Polypharmacy, for example with two or more antipsychotics, might usefully combine diverse pharmacological actions or deliver drug actions at lower overall doses than would be the case for a single agent; it might also combine disadvantageous actions or result in interactions associated with acute or chronic adverse effects. We have been studying the well established and
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distressing increase in mortality associated with psychotic illness; even when risk for suicide is controlled for, patients with psychotic illness are at up to 2-fold increase for death over long-term follow-up. In an initial study of a long-term inpatient population, the maximum number of antipsychotics given concurrently over previous treatment history was associated with reduced survival over the following 10 years. In a subsequent study of a younger, mainly outpatient population, the number of antipsychotics given concurrently at index evaluation did not predict reduced survival over the following 7 years; however, the nature of outpatient care made it difficult to document lifetime medication histories. In our current study, also in a mainly outpatient population, treatment with an antidepressant in addition to a mood stabilizer for bipolar disorder was associated with reduced survival over the following 7 years. Polypharmacy is a complex challenge that requires further systematic study. References [1] Waddington JL, Youssef HA, Kinsella A, 1998, Mortality in schizophrenia in relation to antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry 173, 325–329.
S.17.04 Side effects of antipsychotic polypharmacy F. Drago ° , F. Caraci. University of Catania, Dept. of Experimental and Clinical Pharmacology, Catania, Italy Antipsychotic polypharmacy refers to the use of two or more antipsychotics concurrently in a single patient. The prevalence of antipsychotic polypharmacy has greatly increased, particularly since the advent of the second generation antipsychotics [1]. Treatment resistance, reduction of dose-related side effects caused by antipsychotic monotherapy or the effect on concomitant symptoms of schizophrenia, such as comorbid depression, might justify combination therapy or augmentation strategies. However, antipsychotics are frequently co-prescribed as long-term therapy, a use with little rationale or evidence. Data from literature such as RCTs, naturalistic cohort studies and numerous case reports provide scarce evidence of antipsychotic polypharmacy efficacy [2]. Thus, antipsychotic polypharmacy should not be granted in the management of chronic schizophrenia. Exception can be represented by the association of two antipsychotics, of which one will be shortly replaced by a newly prescribed drug in a therapy switch schedule. Antipsychotic polypharmacy is frequently associated with reduced patient compliance and increased risk of undesired side effects [2]. The complication of the clinical picture is due to the superimposition of different mechanisms of action, i.e. the anticholinergic, the antihistaminergic and the antinoradrenergic mechanisms of antipsychotics [3]. Studies which examined the side effect burden in schizophrenic patients treated with antipsychotic polypharmacy showed higher rates of anticholinergic and extrapyramidal side effects of antipsychotic polypharmacy compared to monotherapy [3]. Antipsychotic polypharmacy has been also implicated in reduced survival, possibly secondary to cardiotoxic effects of antipsychotic medication. Antipsychotic polypharmacy can also increase the potential for negative drug interactions. Side effects associated with combination therapy may themselves require treatment with additional drugs, further complicating the patient’s pharmacological regimen and potentially reducing his compliance.
S202
S.18 Cannabis use in adolescents: effects on brain and behaviour
References [1] Barbui C, Nose M, Mazzi MA, Thornicroft G, Schene A, Becker T, Bindman J, Leese M, Helm H, Koeter M, Weinmann S, Tansella M, 2006, Persistence with polypharmacy and excessive dosing in patients with schizophrenia treated in four European countries. Int Clin Psychopharmacol 21, 355–362. [2] Gardos G, 2005, Antipsychotic polypharmacy or monotherapy? Neuropsychopharmacol Hung 7, 72−77. [3] Stahl SM, Grady MM, 2004, A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation. Curr Med Chem 11, 313–327.
S.17.05 Combination treatments beyond antipsychotic polypharmacy P. Falkai ° , T. Wobrock. University of G¨ottingen, Department of Psychiatry and Psychotherapy, G¨ottingen, Germany Although international guidelines on schizophrenia indicate that monotherapy with antipsychotics should be preferred, in clinical practice most patients receive two and more antipsychotics. There are only few evidence-based recommendations for a targeted combination, primarily based on a theoretical rationale: – Low and high D2-binding: Agents like clozapine demonstrate a relatively low D2-blockade. One way to increase therapeutic efficacy could be to increase D2-blockade by adding substances like haloperidol or risperidone. Concerning the augmentation with risperidone there are some open-label studies and one double-blind controlled study supporting the benefit of this combination but one large scale double-blind study does not. – Loose- and tight-binder: Antipsychotics can be classified whether they bind to the D2-receptor for a longer (e.g. haloperidol, risperidone as tight-binder) or shorter period of time (e.g. quetiapine as a substance with a loose-binding potential). Although this is an interesting concept it is recently questioned whether it can be helpful for combining neuroleptics. – D2-/5HT2- and only D2-modulating neuroleptics: In accordance with the combination of antidepressants one rational could be to combine different modes of actions. There is some evidence from open-label studies that the combination of for instance clozapine with amisulpride is beneficial. In summary, there are theoretical assumptions for a rational combination of neuroleptics in the treatment of schizophrenia. Actually warranted are treatment pathways for schizophrenia in order to reduce the number of treatment resistant patients. Combining neuroleptics is one aspect, but the combination with antidepressants, benzodiazepines and mood stabilizers may be in some respect even more important.
S.18 Cannabis use in adolescents: effects on brain and behaviour S.18.01 Psychoneuroendocrine effects of cannabinoids in critical developmental periods M.P. Viveros ° . Universidad Complutense Facultad de Biolog´ıa, Departamento de Fisiolog´ıa (Fisiolog´ıa Animal II), Madrid, Spain The periadolescent period represents a critical phase in development characterized by increased neurobehavioural plasticity and specific behavioural features, such as enhanced impulsivity and novelty/sensation seeking. During this period, major neuroendocrine changes are taking place and important neural structures and pathways are still developing. Moreover, there appears to be a unique vulnerability to psychological disorders and to the negative effects of psychoactive drugs. Cannabis is one of the most abused drugs among adolescents. Its main psychoactive component, delta 9 tetrahidrocannabinol (delta-9-THC), exerts its effects by activating the cannabinoid CB1 receptors which are densely expressed in brain areas involved in the regulation of emotional responses and brain reward. The endocannabinoid system appears to play a major functional role in maintaining homeostasis, notably as regards modulation of neuroendocrine responses to stress. Thus, challenge of the system by the use of cannabis during a critical developmental period such as adolescence is likely to result in particularly disrupted neuroendocrine function and inadequate emotional responses. In fact, there is strong support for a link between cannabis and the development and exacerbation of psychosis and other neuropsychiatric disorders. Clear associations have been found between cannabis use and the use of other illicit drugs. Experimental studies may contribute to assess whether cannabis might act as a gateway drug. There are intriguing sexual dimorphisms as regards cannabis effects that might influence the pattern and motivations of its consumption. Further systematic investigation of gender differences may help in the establishment of adequate prevention and therapeutical strategies. References [1] Marco EM, Granstrem O, Moreno E, Llorente R, Adriani W, Laviola G, Viveros MP, 2007, Subchronic nicotine exposure in adolescence induces long-term effects on hippocampal and striatal cannabinoid-CB1 and mu-opioid receptors in rats. Eur J Pharmacol 557, 37−43. [2] Viveros MP, Llorente R, Moreno E, Marco EM, 2005, Behavioural and neuroendocrine effects of cannabinoids in critical developmental periods. Behav Pharmacol 16, 353−62. [3] Viveros MP, Marco EM, File SE, 2006, Nicotine and cannabinoids: parallels, contrasts and interactions. Neurosci Biobehav Rev 30, 1161−81.
References [1] Falkai P, Wobrock T Lieberman J, Glenthoj B, Gattaz WF, Moller HJ; WFSBP Task Force on Treatment Guidelines for Schizophrenia, 2005, World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, Part 1: acute treatment of schizophrenia. World J Biol Psychiatry 6, 132–191. Review.
S.18.02 Cannabis effects on brain function and structure of adolescents and young adults R.I. Block1 ° , D.S. O’Leary2 , G. Jager3 , J.M. Zuccarelli1 , M.M. Becker1 , M. Luijten3 , N.F. Ramsey3 . 1 University of Iowa, Department of Anesthesia, Iowa City, USA; 2 University of Iowa, Department of Psychiatry, Iowa City, USA; 3 University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience Department of Neurosurgery, Utrecht, The Netherlands We are conducting a United States – Netherlands collaborative functional magnetic resonance imaging (MRI) research study to examine the effects of chronic cannabis use on brain function