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P.3.d.017 Aripiprazole augmentation of clozapine in treatment-resistant schizophrenia patients – two case reports and discussion
S530
P.3.d. Psychotic disorders and treatment − Treatment (clinical)
approved by the institutional review board of each center. Subjects were being treated with antipsychotics − risperidone, olanzapine, and aripiprazole − at least 2 weeks and switched to paliperidone. Levels of plasma prolactin were measured at baseline, week 12, and at week 24. All data were analyzed using SPSS 20.0 for Windows. One way ANOVA was used for evaluating the demographic characteristics. The changes of prolactin levels were analyzed using repeated-measures ANOVA depends on different time spans. We used linear mixed model for calculating the effect of time by group interaction. The significance level was set at <0.05. Results: In overall patients, after switching to paliperidone, the level of prolactin was increased at week 12 yet decreased at week 24. These results were statistically significant, according to time flow. For the comparisons of the three groups which were classified according to previous antipsychotics, sex, age, and age at onset of symptoms were not different statistically (sex: p = 0.710, age: p = 0.179, age at onset of symptoms: p = 0.560). However, the baseline prolactin levels were found statistically different in all three groups of risperidone, olanzapine, and aripiprazole (p < 0.001). Also, there was an effect of the interaction between time and groups (p < 0.001). Additionally, the same pattern of results was detected during the investigation of male and female patients, respectively (male: p < 0.001, female: p < 0.001). Conclusion: This study suggests that the plasma level of prolactin would be elevated and tolerance could be developed in schizophrenia or schizophreniform patients who are taking pariperidone. In addition, the changes in plasma prolactin level are affected by time spans and antipsychotics taken previously. Also, the gender differences were not detected in this study. Further research using objective measures, such as levels of sex hormones, with larger samples undergoing longterm treatment with paliperidone may provide more evidence. References [1] Wieck A, Haddad PM. Antipsychotic-induced hyperprolactinemia inwomen: pathophysiology, severity and consequences. Selective literaturereview. Br J Psychiatry 2003; 182: 199–204. [2] Haddad P M, Wieck A. Antipsychotic-induced hyperprolactinemia:mechanisms, clinical features and management. Drugs 2004; 64: 2291–2314. [3] Hummer M, Huber J. Hyperprolactinemia and antipsychotic therapyin schizophrenia. Curr Med Res Opin 2004; 20: 189–197.
in a phase III study HGKA and it’s open-label follow-up study HGKBwith respect to efficacy and safety of olanzapine LAI, where patients who responded well to the compound and approved, were allowed to continue treatment until olanzapine LAI was introduced on the market. The patients who continued treatment have been followed with respect to remission, a new episode, hospitalization, hospital days, post-injection syndromes, discomfort from the injection site and satisfaction with the medication. Methods: In a mirrorimage study 48 patients treated with olanzapine LAI were followed with respect to adherence, duration of treatment with olanzapine LAI (in months), relapse rates and hospital days before and after change in medication. Summary of results: Included patients were diagnosed according to DSM-IV [3] and all fulfilled the diagnostic criteria of schizophrenia. Thirty-nine patients were men and nine were women. Mean age was 43.6 years (range 22−72 years) and mean duration of illness was 14.1years (range 1−52 years) years. Before olanzapine LAI was initiated 31 patients were treated with per oral medication and 17 with a depot, 31 patients were prescribed atypical antipsychotics and 17 typical antipsychotics. Adherence was rated by the psychiatrist in charge, before and after treatment with olanzapine LAI. Before olanzapine LAI treatment adherence was rated as poor in 30 patients. Adherence increased after change in treatment. The mean daily dose of olanzapine LAI was 258 mg (range 75–405 mg) every second week. Hospital days decreased from a mean value of 163 to 119 days from period 1 to period 2. Conclusions: Poor adherence during maintenance treatment of schizophrenia exposing patients to a high risk of relapse, rehospitalization and other negative outcomes. This has lead to a reawakening of the potential of the use of long-acting injectable antipsychotics. During treatment with olanzapine LAI days in hospital decreased significantly, from 7824 days before to 5689 days after for all included 48 patients. This gives a mean value of 163 days before start treatment with olanzapine LAI and 119 after. Since time in hospital is the most expensive part of total costs this is a saving of a total of 1,206,000 Euro (10,675,000 SEK)*. This means a substantial saving of 25,134 Euro (223,396 SEK)* per included patient. *Costs are calculated based on an average psychiatric hospital bed in Sweden, an amount of 565 Euro/day. References
P.3.d.016 Olanzapine LAI: hospital days and health economic aspects during long-term treatment: a multi-center mirror study P.A. Karlsson1 ° , M. Javadi2 , T. Liljekvist3 , C. Lehman4 , ¨ S. Olsson5 , E. Lindstrom5 1 Forensic Psychiatry, Ojebyn, Sweden; 2 Psychiatric clinic PVE Sodermalm, Stockholm, Sweden; 3 Psychiatric clinic, Sundsvall, Sweden; 4 Forensic clinic, Sundsvall, Sweden; 5 Uppsala university hospital, Neuroscience, Uppsala, Sweden Purpose of the study: The main purpose of the study was to investigate if a long-acting injectable, olanzapine LAI, could increase long time adherence and decrease hospital days. Nonadherence in patients with schizophrenia is associated with increased hospitalization, higher heatlh care costs [1], progressive cortical decrease, suicide and higher overall mortality [2].Olanzapine pamoate monohydrate, a novel antipsychotic long-acting injectable (LAI), has been available for use in Sweden since 2010. Before introduction on the market Swedish clinics participated
[1] Sun SX, Liu nGG, Christenssen DB, FU AZ. Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States. Curr. Med. Res. Opin. 2007:23:2305–2312. [2] Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P. A nation widecohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psych 2011; 168: 603–609. [3] American Psychiatric Association. Diagnostic and Statistical Manual of Psychiatric Disorders. Fourth edition. Washington DC 1994. Disclosure statement: Member of Lilly advisory board.
P.3.d.017 Aripiprazole augmentation of clozapine in treatment-resistant schizophrenia patients − two case reports and discussion K. Todorova-Nenova1 ° , M. Arnaoudova1 “St. Marina”, Varna, Bulgaria
1 University
Hospital
Background and Purpose: Antipsychotic drugs elicit an inadequate response in 20−40% of people suffering from schizophrenia. Clozapine is still the gold standard in treatment-resistant
P.3.d. Psychotic disorders and treatment − Treatment (clinical) schizophrenia but however, a considerable number of patients are nonresponsive or only partially responsive to the medication and continue to experience a high level of positive symptoms [1]. The combined application of antipsychotic drugs is a common treatment strategy in an attempt to improve response to treatment in this patient group [2]. Clozapine has a unique broad-spectrum receptor-binding profile with relatively low affinities to D2 receptors. Aripiprazole has greater affinity for D2 receptors and based on its overall pharmacological profile is termed as one of a new class of atypical antipsychotic agents acting as dopamineserotonine system stabilizers [3]. Methods: A review of the literature on the aripiprazole augmentation of clozapine in treatment-resistant schizophrenia and presentation of two case reports. Summary of results: The retrieved information from the literature was scarce and in our consideration the risk of bias was high, based on the small sample size, variable definitions of clozapine resistance, heterogeneity of outcome measures and methodological designs. Although a common strategy, the combined administration of antipsychotic drugs in treatment-resistant schizophrenia seemed in contrast with most published clinical guidelines. Most authors shared the conclusion that combined application of clozapine and aripiprazole was in accordance with a neurobiological rationale and appeared to be safe and well tolerated without increased risk of adverse effects. Testing this hypothesis we report our first observations with the combination of clozapine and aripiprazole in two patients with treatment-resistant schizophrenia. Two patients of our inpatient clinic with paranoid schizophrenia (33 years and 38 years, meeting ICD-10 diagnostic criteria) were found to be resistant to the application of several typical and atypical antipsychotics. A suboptimal response to clozapine treatment (450 mg and 400 mg daily dosage respectively) was registered over the last 12 months with persistent paranoid delusions and accustic hallucinations. Additionally one of the patients experienced an exacerbation of catatonic stereotypies, almost preventing her from leaving home. The phychiatric condition of the patients required hospitalization. Up-titration of clozapine was unsuccessful because of side effects (sedation and hypersalivation). Fifteen milligram aripiprazole daily was added. Positive symptoms decreased within four weeks. The improvement of the catatonic stereotypies followed in a week after the initiation of aripiprazole, allowing patient’s outdoor walks. Subsequently the daily dose of clozapine was slightly reduced in both patients (400 mg and 350 mg respectively), which led to the reduction of side effects (daytime sedation, hypersalivation and weight gain) and ensured better quality of life. Conclusion: The reported two treatment resistant schizophrenia cases emphasize the importance of making interventions based on individual patient’s response. The combined application of the two drugs followed a neurobiological rationale with a synergic antipsychotic potency which appeared to benefit the patients without increasing the rate of side effects. The risk/benefit evaluation of the patients’ condition may require a longer period to be thoroughly assessed. References [1] Ballon, J., Lieberman, J., 2010 Advances in the management of treatment-resistant schizophrenia. Focus 8, 475–487. [2] Cipriani, A., Boso, M., Barbui, C., 2009 Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia. Cochrane Database Syst Rev 3:CD006324. doi: 10.1002/14651858. CD006324.pub2.
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[3] Ziegenbein, M., Wittmann, G., Kropp, S., 2006 Aripiprazole augmentation of Clozapine in treatment-resistant schizophrenia: a clinical observation. Clin Drug Investig 26, 117–124.
P.3.d.018 Phase 2 clinical trial of TC-5619, an alpha 7 nicotinic receptor agonist in the treatment of negative and cognitive symptoms in schizophrenia D. Hosford1 ° , C. Dvergsten1 , J. Beaver1 , A.C. Segreti1 , S. Toler2 , M.G. Farr1 , M. Joseph2 , J. Jett2 , P. Lippiello2 , M. Bencherif3 1 Targacept Inc., Clinical Development and Regulatory Affairs, Winston Salem N.C., USA; 2 Targacept Inc., Clinical Pharmaceutical Sciences, Winston Salem N.C., USA; 3 Targacept Inc., Preclinical Science, Winston Salem N.C., USA Background: There are no approved medicines to treat negative symptoms or cognitive dysfunction in people with schizophrenia. These are common features of the condition that often prevent those whose positive symptoms are well-controlled from resuming or achieving their premorbid potential. TC-5619, a selective alpha 7 nicotinic receptor agonist, showed statistically significant benefit in preclinical models of cognition and of negative symptoms; and also showed statistically significant benefit in cognitive and negative symptoms in an early phase 2 adjunctive clinical trial in schizophrenia that was conducted in the US and India [1]. Methods: This phase 2B clinical trial was a double-blind, randomized, parallel group, fixed dose, placebo-controlled trial comparing TC-5619 vs. placebo in the adjunctive treatment of negative symptoms or cognitive dysfunction in well-controlled outpatients with schizophrenia. Sixty-six sites in the US, Russia, Ukraine, Hungry, Romania and Serbia randomized 477 patients into a 24-week treatment period in which they received either TC-5619 (5 mg [n = 121] or 50 mg [n = 121]) or placebo [n = 235] per os once daily in a 1:1:2 ratio. All atypical antipsychotics were permitted except clozapine. The primary outcome measure, negative symptoms, was measured using the Scale to Assess Negative Symptoms (SANS), and the key secondary outcome measures, cognition and functional ability, were measured using the Cogstate Schizophrenia Test Battery (CSTB) and the UCSD Performance-Based Skills Assessment-Brief version (UPSA-B). A variety of other efficacy and safety measures included global clinical outcome, adverse events, vital signs, physical exam, laboratory and ECG measurements, movement disorders, suicidality, depression, and tobacco craving. Results: The majority of the randomized subjects were tobacco users and the demographic profile was consistent with other trials in this population. None of the primary, key secondary or secondary efficacy outcome measures showed a statistically significant benefit favoring either dose of TC-5619. The SANS composite score showed a decrease (improvement) from baseline (70 points) at 24 weeks of 15.4 points (placebo), 17.5 points (TC5619, 5 mg, p = 0.16), and 14.7 points (TC-5619, 50 mg, p = 0.69). CSTB composite score showed an increase (improvement) from baseline (0 points) at 24 weeks of 0.19 points (placebo), 0.08 points (TC-5619, 5 mg, p = 0.38), and 0.26 points (TC-5619, 50 mg, p = 0.55). UPSA-B total score showed an increase (improvement) from baseline (69 points) of 10.9 points (placebo), 12.4 points (TC-5619, 5 mg, p = 0.23), and 10.5 points (TC-5619, 50 mg, p = 0.74). Withdrawals from the trial, including those due to adverse events, were low, and there were few serious adverse events.
P.3.d. Psychotic disorders and treatment − Treatment (clinical)
approved by the institutional review board of each center. Subjects were being treated with antipsychotics − risperidone, olanzapine, and aripiprazole − at least 2 weeks and switched to paliperidone. Levels of plasma prolactin were measured at baseline, week 12, and at week 24. All data were analyzed using SPSS 20.0 for Windows. One way ANOVA was used for evaluating the demographic characteristics. The changes of prolactin levels were analyzed using repeated-measures ANOVA depends on different time spans. We used linear mixed model for calculating the effect of time by group interaction. The significance level was set at <0.05. Results: In overall patients, after switching to paliperidone, the level of prolactin was increased at week 12 yet decreased at week 24. These results were statistically significant, according to time flow. For the comparisons of the three groups which were classified according to previous antipsychotics, sex, age, and age at onset of symptoms were not different statistically (sex: p = 0.710, age: p = 0.179, age at onset of symptoms: p = 0.560). However, the baseline prolactin levels were found statistically different in all three groups of risperidone, olanzapine, and aripiprazole (p < 0.001). Also, there was an effect of the interaction between time and groups (p < 0.001). Additionally, the same pattern of results was detected during the investigation of male and female patients, respectively (male: p < 0.001, female: p < 0.001). Conclusion: This study suggests that the plasma level of prolactin would be elevated and tolerance could be developed in schizophrenia or schizophreniform patients who are taking pariperidone. In addition, the changes in plasma prolactin level are affected by time spans and antipsychotics taken previously. Also, the gender differences were not detected in this study. Further research using objective measures, such as levels of sex hormones, with larger samples undergoing longterm treatment with paliperidone may provide more evidence. References [1] Wieck A, Haddad PM. Antipsychotic-induced hyperprolactinemia inwomen: pathophysiology, severity and consequences. Selective literaturereview. Br J Psychiatry 2003; 182: 199–204. [2] Haddad P M, Wieck A. Antipsychotic-induced hyperprolactinemia:mechanisms, clinical features and management. Drugs 2004; 64: 2291–2314. [3] Hummer M, Huber J. Hyperprolactinemia and antipsychotic therapyin schizophrenia. Curr Med Res Opin 2004; 20: 189–197.
in a phase III study HGKA and it’s open-label follow-up study HGKBwith respect to efficacy and safety of olanzapine LAI, where patients who responded well to the compound and approved, were allowed to continue treatment until olanzapine LAI was introduced on the market. The patients who continued treatment have been followed with respect to remission, a new episode, hospitalization, hospital days, post-injection syndromes, discomfort from the injection site and satisfaction with the medication. Methods: In a mirrorimage study 48 patients treated with olanzapine LAI were followed with respect to adherence, duration of treatment with olanzapine LAI (in months), relapse rates and hospital days before and after change in medication. Summary of results: Included patients were diagnosed according to DSM-IV [3] and all fulfilled the diagnostic criteria of schizophrenia. Thirty-nine patients were men and nine were women. Mean age was 43.6 years (range 22−72 years) and mean duration of illness was 14.1years (range 1−52 years) years. Before olanzapine LAI was initiated 31 patients were treated with per oral medication and 17 with a depot, 31 patients were prescribed atypical antipsychotics and 17 typical antipsychotics. Adherence was rated by the psychiatrist in charge, before and after treatment with olanzapine LAI. Before olanzapine LAI treatment adherence was rated as poor in 30 patients. Adherence increased after change in treatment. The mean daily dose of olanzapine LAI was 258 mg (range 75–405 mg) every second week. Hospital days decreased from a mean value of 163 to 119 days from period 1 to period 2. Conclusions: Poor adherence during maintenance treatment of schizophrenia exposing patients to a high risk of relapse, rehospitalization and other negative outcomes. This has lead to a reawakening of the potential of the use of long-acting injectable antipsychotics. During treatment with olanzapine LAI days in hospital decreased significantly, from 7824 days before to 5689 days after for all included 48 patients. This gives a mean value of 163 days before start treatment with olanzapine LAI and 119 after. Since time in hospital is the most expensive part of total costs this is a saving of a total of 1,206,000 Euro (10,675,000 SEK)*. This means a substantial saving of 25,134 Euro (223,396 SEK)* per included patient. *Costs are calculated based on an average psychiatric hospital bed in Sweden, an amount of 565 Euro/day. References
P.3.d.016 Olanzapine LAI: hospital days and health economic aspects during long-term treatment: a multi-center mirror study P.A. Karlsson1 ° , M. Javadi2 , T. Liljekvist3 , C. Lehman4 , ¨ S. Olsson5 , E. Lindstrom5 1 Forensic Psychiatry, Ojebyn, Sweden; 2 Psychiatric clinic PVE Sodermalm, Stockholm, Sweden; 3 Psychiatric clinic, Sundsvall, Sweden; 4 Forensic clinic, Sundsvall, Sweden; 5 Uppsala university hospital, Neuroscience, Uppsala, Sweden Purpose of the study: The main purpose of the study was to investigate if a long-acting injectable, olanzapine LAI, could increase long time adherence and decrease hospital days. Nonadherence in patients with schizophrenia is associated with increased hospitalization, higher heatlh care costs [1], progressive cortical decrease, suicide and higher overall mortality [2].Olanzapine pamoate monohydrate, a novel antipsychotic long-acting injectable (LAI), has been available for use in Sweden since 2010. Before introduction on the market Swedish clinics participated
[1] Sun SX, Liu nGG, Christenssen DB, FU AZ. Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States. Curr. Med. Res. Opin. 2007:23:2305–2312. [2] Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P. A nation widecohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psych 2011; 168: 603–609. [3] American Psychiatric Association. Diagnostic and Statistical Manual of Psychiatric Disorders. Fourth edition. Washington DC 1994. Disclosure statement: Member of Lilly advisory board.
P.3.d.017 Aripiprazole augmentation of clozapine in treatment-resistant schizophrenia patients − two case reports and discussion K. Todorova-Nenova1 ° , M. Arnaoudova1 “St. Marina”, Varna, Bulgaria
1 University
Hospital
Background and Purpose: Antipsychotic drugs elicit an inadequate response in 20−40% of people suffering from schizophrenia. Clozapine is still the gold standard in treatment-resistant
P.3.d. Psychotic disorders and treatment − Treatment (clinical) schizophrenia but however, a considerable number of patients are nonresponsive or only partially responsive to the medication and continue to experience a high level of positive symptoms [1]. The combined application of antipsychotic drugs is a common treatment strategy in an attempt to improve response to treatment in this patient group [2]. Clozapine has a unique broad-spectrum receptor-binding profile with relatively low affinities to D2 receptors. Aripiprazole has greater affinity for D2 receptors and based on its overall pharmacological profile is termed as one of a new class of atypical antipsychotic agents acting as dopamineserotonine system stabilizers [3]. Methods: A review of the literature on the aripiprazole augmentation of clozapine in treatment-resistant schizophrenia and presentation of two case reports. Summary of results: The retrieved information from the literature was scarce and in our consideration the risk of bias was high, based on the small sample size, variable definitions of clozapine resistance, heterogeneity of outcome measures and methodological designs. Although a common strategy, the combined administration of antipsychotic drugs in treatment-resistant schizophrenia seemed in contrast with most published clinical guidelines. Most authors shared the conclusion that combined application of clozapine and aripiprazole was in accordance with a neurobiological rationale and appeared to be safe and well tolerated without increased risk of adverse effects. Testing this hypothesis we report our first observations with the combination of clozapine and aripiprazole in two patients with treatment-resistant schizophrenia. Two patients of our inpatient clinic with paranoid schizophrenia (33 years and 38 years, meeting ICD-10 diagnostic criteria) were found to be resistant to the application of several typical and atypical antipsychotics. A suboptimal response to clozapine treatment (450 mg and 400 mg daily dosage respectively) was registered over the last 12 months with persistent paranoid delusions and accustic hallucinations. Additionally one of the patients experienced an exacerbation of catatonic stereotypies, almost preventing her from leaving home. The phychiatric condition of the patients required hospitalization. Up-titration of clozapine was unsuccessful because of side effects (sedation and hypersalivation). Fifteen milligram aripiprazole daily was added. Positive symptoms decreased within four weeks. The improvement of the catatonic stereotypies followed in a week after the initiation of aripiprazole, allowing patient’s outdoor walks. Subsequently the daily dose of clozapine was slightly reduced in both patients (400 mg and 350 mg respectively), which led to the reduction of side effects (daytime sedation, hypersalivation and weight gain) and ensured better quality of life. Conclusion: The reported two treatment resistant schizophrenia cases emphasize the importance of making interventions based on individual patient’s response. The combined application of the two drugs followed a neurobiological rationale with a synergic antipsychotic potency which appeared to benefit the patients without increasing the rate of side effects. The risk/benefit evaluation of the patients’ condition may require a longer period to be thoroughly assessed. References [1] Ballon, J., Lieberman, J., 2010 Advances in the management of treatment-resistant schizophrenia. Focus 8, 475–487. [2] Cipriani, A., Boso, M., Barbui, C., 2009 Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia. Cochrane Database Syst Rev 3:CD006324. doi: 10.1002/14651858. CD006324.pub2.
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[3] Ziegenbein, M., Wittmann, G., Kropp, S., 2006 Aripiprazole augmentation of Clozapine in treatment-resistant schizophrenia: a clinical observation. Clin Drug Investig 26, 117–124.
P.3.d.018 Phase 2 clinical trial of TC-5619, an alpha 7 nicotinic receptor agonist in the treatment of negative and cognitive symptoms in schizophrenia D. Hosford1 ° , C. Dvergsten1 , J. Beaver1 , A.C. Segreti1 , S. Toler2 , M.G. Farr1 , M. Joseph2 , J. Jett2 , P. Lippiello2 , M. Bencherif3 1 Targacept Inc., Clinical Development and Regulatory Affairs, Winston Salem N.C., USA; 2 Targacept Inc., Clinical Pharmaceutical Sciences, Winston Salem N.C., USA; 3 Targacept Inc., Preclinical Science, Winston Salem N.C., USA Background: There are no approved medicines to treat negative symptoms or cognitive dysfunction in people with schizophrenia. These are common features of the condition that often prevent those whose positive symptoms are well-controlled from resuming or achieving their premorbid potential. TC-5619, a selective alpha 7 nicotinic receptor agonist, showed statistically significant benefit in preclinical models of cognition and of negative symptoms; and also showed statistically significant benefit in cognitive and negative symptoms in an early phase 2 adjunctive clinical trial in schizophrenia that was conducted in the US and India [1]. Methods: This phase 2B clinical trial was a double-blind, randomized, parallel group, fixed dose, placebo-controlled trial comparing TC-5619 vs. placebo in the adjunctive treatment of negative symptoms or cognitive dysfunction in well-controlled outpatients with schizophrenia. Sixty-six sites in the US, Russia, Ukraine, Hungry, Romania and Serbia randomized 477 patients into a 24-week treatment period in which they received either TC-5619 (5 mg [n = 121] or 50 mg [n = 121]) or placebo [n = 235] per os once daily in a 1:1:2 ratio. All atypical antipsychotics were permitted except clozapine. The primary outcome measure, negative symptoms, was measured using the Scale to Assess Negative Symptoms (SANS), and the key secondary outcome measures, cognition and functional ability, were measured using the Cogstate Schizophrenia Test Battery (CSTB) and the UCSD Performance-Based Skills Assessment-Brief version (UPSA-B). A variety of other efficacy and safety measures included global clinical outcome, adverse events, vital signs, physical exam, laboratory and ECG measurements, movement disorders, suicidality, depression, and tobacco craving. Results: The majority of the randomized subjects were tobacco users and the demographic profile was consistent with other trials in this population. None of the primary, key secondary or secondary efficacy outcome measures showed a statistically significant benefit favoring either dose of TC-5619. The SANS composite score showed a decrease (improvement) from baseline (70 points) at 24 weeks of 15.4 points (placebo), 17.5 points (TC5619, 5 mg, p = 0.16), and 14.7 points (TC-5619, 50 mg, p = 0.69). CSTB composite score showed an increase (improvement) from baseline (0 points) at 24 weeks of 0.19 points (placebo), 0.08 points (TC-5619, 5 mg, p = 0.38), and 0.26 points (TC-5619, 50 mg, p = 0.55). UPSA-B total score showed an increase (improvement) from baseline (69 points) of 10.9 points (placebo), 12.4 points (TC-5619, 5 mg, p = 0.23), and 10.5 points (TC-5619, 50 mg, p = 0.74). Withdrawals from the trial, including those due to adverse events, were low, and there were few serious adverse events.