- Email: [email protected]
P.3.21 The effect of clozapine on factorscontrolling glucose homeostasis
Clinical Neuropsychopharmacology battery (MARS; Rubia et al., 2001) measuring motor and cognitive inhibition, reward and time estimation, that have shown to elicit cognitive and neurocognitive impairment in subjects with ADHD, and shown to be improved with MPH in neuropsychological studies. Methods: Event related fMRI was used in a double blind, randomised, placebo controlled study to investigate the effect of MPH on functional brain activation in eight right handed medication naive boys (aged 10-14), with a DSM IV diagnosis of ADHD. Subjects were scanned twice, one week apart, after ingestion of either placebo or 0.3 mg/kg of MPH. A 1.5 T GE system acquired fMRI data during four tasks assessing motor (stop task) and cognitive inhibition (stroop task), reward and time estimation. Repeated measures ANOVA was used for cluster level comparisons at p<0.01. Results: While behavioural performance was comparable, with the exception of a positive effect of MPH on the speed of executive and inhibitory performance on the stop task, differences in brain function were observed in response to medicatiorL MPH compared to placebo significantly increased brain activation in the basal ganglia, thalamus and anterior cingulate gyms during stop, stroop and time estimation tasks, with additional activation in medial frontal lobe during stop task and time estimation and inferior parietal lobe during stroop task performance. During the reward task, significant activation increase with MPH was elicited in the cerebellum. Compared to medication, the placebo condition activated posterior brain regions such as temporal, parietal and occipital cortices and brainstem. Conclusions: MPH appears to increase task-specific functional brain activation in ADHD in the basal ganglia (stop, stroop, time estimation), prefrontal cortex and anterior cingulate (stop, time estimation) and the cerebellum (reward, stroop), brain areas that are known to have relatively high density of dopamine transporters and have shown to be abnormal in their function (Rubia et al., 1999) and structure in children with ADHD.
References [1] Rubia, K., Taylor, E., Smith, A.B., Oksanen, H., Overmeyer, S., Newman, S., Oksannen, H., 2001. Neuropsychological analyses of impulsiveness in childhood hyperactivity. Br J Psychiatr 179, 138-143. [2] Vaidya, C.J., Austin, G., Kirkorian, G., Ridlehuher, H.W., Desmond, J.E., Glover, G.H., Gabrieli, J.D., 1998. Selective effects of methylphenidate in attention deficit hyperactivity disorder: a functional magnetic resonance study. Proc Natl Acad Sci USA 95, 14494-14499. [3] Rubia, K., Overmeyer, S., Taylor, E., Brammer, M,, Williams, S.C., Simmons, A., Bullmore, E.T.,
$67
1999. Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. Am J Psychiatr 156, 891-6.
effect of clozapine on factors P•-.3.•-I The controlling glucose homeostasis O.D. Howes, A. Bhatnagar, ER Gaughran, S. Amiel, R,M. Murray, L.S. Pilowsky. Department of
Psychological Medicine, Institute of Psychia#y, Camberwell, London, UK Objectives: This prospective study examines the effect of clozapine on factors determining glucose homeostasis. Insulin, insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-1 (IGFBP-1), and growth hormone (GH) are important glucoregulatory factors that some authors have suggested may be altered by clozapine leading to glucose dysregulation. IGF-1 levels have been found to be significantly lower in patients taking clozapine compared to patients taking classical antipsychotics. No study has assessed IGF-1, IGFBP-1, and GH levels prospectively, at baseline and again following initiation of clozapine to establish whether abnormalities in these factors are related to clozapine treatment. If clozapine alters IGF-1, IGFBP-1, and GH levels this would further understanding of the mechanism by which clozapine affects glucose control and weight. This study aims to be the first to evaluate glucose control and hormonal regulatory factors prospectively. Method: The sample consisted of all patients commencing clozapine within the South London and Maudsley hospitals during one year. Insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) were measured in 20 patients (mean age 30.5 yrs, SD=7.4, 45% female) before, and after, an average of 2.5 (SD=0.95)months of clozapine treatment. Insulin resistance was assessed using the homeostasis model assessment (HOMA-IR). Results: Fifty-five per cent of subjects developed abnormal glucose control (n=ll, mean age 30.2, SD=7.1, 46% female). Patients showed insulin resistance at baseline (mean HOMA-IR level=3.88, SD=2.93), which was unaffected by clozapine (p=0.37). Mean fasting and 2-hour glucose levels increased by 0.55 retool/1 (p=0.01) and 1.4 retool/1 (p=0.002) respectively, and there was no correlation between change in weight and change in fasting (r=0.17, p=0.49) or 2-hour glucose levels (r=0.37, p=0.14). Baseline IGFBP-1 was low (3.1 ~tg/1, SD=3.7; expected value >15), indicating long-term insulin resistance. GH (t=l.8, df=15, p=0.088), IGF-1 (t=0.58, df=15, p=0.57), and IGFBP-1 (t=l.2, df=l 5, p=0.24)were not significantly
868
Clinical Neuropsychopharmacology
changed by elozapine treatment. There was no correlation between elozapine blood levels and insulin (p=0.5), GH (p=0.7), IGF-1 (p=0.5), or IGFBP-1 (Io=0.5) levels on elozapine. Conclusions: Clozapine treatment is associated with the development of new onset abnormal glucose control in 55% of subjects within 3 months of initiation, which was not associated with weight gain. Fasting glucose levels are increased, and a prolonged hyperglycaemic peak is seen following clozapine initiation. Patients showed evidence of insulin resistance at baseline, which may be related to prior treatment with antipsychotics or the disease process seen in refractory schizophrenia. Clozapine treatment was not associated with alterations in insulin, GH, IGF, or IGFBP-1. The absence of the expected hormonal compensatory response to increased glucose levels is concerning and suggests that alterations in glucoregulation are occurring proximal to the hormonal regulation of glt~ose levels. Clozapine has been found to inhibit glucose transport into neuronal cell lines [1]. We hypothesise that clozapine impairs glucose transport into the glucose sensing neurones, thereby increasing the threshold for initiation of the hormonal homeostatic mechanisms. This mechanism would explain the rapid increase in plasma glt~ose level independent of changes in hormonal levels.
References [1] Dwyer DS, Pink&sky HB, Liu Y, Bradley RJ. Antipsychotic drugs affect glucose uptake and the expression of glucose transporters in PC12 cells. Prog Neuropsychopharmacol Biol Psychiatr 1999; 23: 69-80.
IP.3.221 Predictive factors of resistance to antidepressant treatment: results from a European multicentre study P. O s w a l d 1 , D. S o u e r y 1 , S. K a s p e r 2, Y. Lecrubier 3,
J. Zohar 4, J. Mendlewicz 1. On behalf of the Group for
the Study of Resistant Depression (GSRD). 1Department of Psychiatry, Unioersity Clinics of Brussels, Erasme Hospital, Free Unioersity of Brussels, Brussels, Belgium; 2Department of General Psychiatry, Unioersity Hospital for Psychiatry, Vienna, Austria; 3INSERM, Hdpital de la Salpgtri~re, Paris, France; 4Chaim Sheba Medical Centre, Dioision of Psychiatry, Tel Hashomer, Israel When adequately treated, up to half of all patients with major depression do not respond adequately to first-line antidepressant (AD). However, research on resistance to AD treatment has been marked with inconsistent findings, mainly due to the plethora of definitions of treatment
resistant depression (TRD) (Rush et al., 2003). During the last decade, a consensus has been raised defining TRD as the failure to respond to at least two consecutive adequate A D from different classes (Souery et al., 1999). This definition allows the investigation of clinical predicting factors of TRD. We initiated a study including seven European centres: Brussels, Sint-Truiden, Leuven, TelAviv, Paris, Vienna and Milan. A total of 996 patients with major unipolar depression having received at least one adequate AD treatment for the current episode were recruited. All patients were evaluated using the MINI (Mini International Neuropsychiatric Interview, a validated structured diagnostic interview, providing an accurate DSM-IV diagnosis (Sheehan et al., 1998). An exhaustive questionnaire was applied investigating more than 200 factors including: 1) demographic and psychosocial characteristics, 2) data on the current depressive episode, including psychiatric comorbidities, personality dimensions and somatic comorbidities, 3) personal and family history of psychiatric disorders, 4) data on current and past antidepressant and other psychotropic treatments. According to the definition of TRD, a logistic regression model was applied for which we excluded a sample of 112 patients, because they were non responder to a single and unique AD treatment, and another sample of 254 patients, because of partial missing data used for the categorization in resistant or non resistant patients. 276 unipolar patients were considered as resistant and 354 as non resistant (responder to a first or single A D or non responder to a first A D but responder to a second AD). We found that current melancholia (p=0.01), severe intensity (p=.006), current suicide risk (p<0.0001), current panic disorder (p<0.0001), current anxiety disorder (p<0.0001), a low educational level (p=0.01), personality disorder (p=0.05), current hospitalization (p=0.001), family history &bipolar disorder (p=0.05) and suicide (p=0.05), absence of response to a first antidepressant lifetime (p=0.02) and early age at onset (<16 yo, p<0.001; <18 yo, p<0.001) predict the occurrence of TRD in our unipolar sample. In a multifactorial logistic regression model, a current panic disorder, a current suicide risk and an early age at onset (<16 yo and <18 yo) were found to be the major risk factors in TRD. This is, to our knowledge, the first study investigating a large number &potential predictive factors of TRD in a multicentre European study, involving a large sample of patients with major unipolar depression. Supported by an tw~restricted grant from Lundbeck.
References [1] Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview
References [1] Rubia, K., Taylor, E., Smith, A.B., Oksanen, H., Overmeyer, S., Newman, S., Oksannen, H., 2001. Neuropsychological analyses of impulsiveness in childhood hyperactivity. Br J Psychiatr 179, 138-143. [2] Vaidya, C.J., Austin, G., Kirkorian, G., Ridlehuher, H.W., Desmond, J.E., Glover, G.H., Gabrieli, J.D., 1998. Selective effects of methylphenidate in attention deficit hyperactivity disorder: a functional magnetic resonance study. Proc Natl Acad Sci USA 95, 14494-14499. [3] Rubia, K., Overmeyer, S., Taylor, E., Brammer, M,, Williams, S.C., Simmons, A., Bullmore, E.T.,
$67
1999. Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. Am J Psychiatr 156, 891-6.
effect of clozapine on factors P•-.3.•-I The controlling glucose homeostasis O.D. Howes, A. Bhatnagar, ER Gaughran, S. Amiel, R,M. Murray, L.S. Pilowsky. Department of
Psychological Medicine, Institute of Psychia#y, Camberwell, London, UK Objectives: This prospective study examines the effect of clozapine on factors determining glucose homeostasis. Insulin, insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-1 (IGFBP-1), and growth hormone (GH) are important glucoregulatory factors that some authors have suggested may be altered by clozapine leading to glucose dysregulation. IGF-1 levels have been found to be significantly lower in patients taking clozapine compared to patients taking classical antipsychotics. No study has assessed IGF-1, IGFBP-1, and GH levels prospectively, at baseline and again following initiation of clozapine to establish whether abnormalities in these factors are related to clozapine treatment. If clozapine alters IGF-1, IGFBP-1, and GH levels this would further understanding of the mechanism by which clozapine affects glucose control and weight. This study aims to be the first to evaluate glucose control and hormonal regulatory factors prospectively. Method: The sample consisted of all patients commencing clozapine within the South London and Maudsley hospitals during one year. Insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) were measured in 20 patients (mean age 30.5 yrs, SD=7.4, 45% female) before, and after, an average of 2.5 (SD=0.95)months of clozapine treatment. Insulin resistance was assessed using the homeostasis model assessment (HOMA-IR). Results: Fifty-five per cent of subjects developed abnormal glucose control (n=ll, mean age 30.2, SD=7.1, 46% female). Patients showed insulin resistance at baseline (mean HOMA-IR level=3.88, SD=2.93), which was unaffected by clozapine (p=0.37). Mean fasting and 2-hour glucose levels increased by 0.55 retool/1 (p=0.01) and 1.4 retool/1 (p=0.002) respectively, and there was no correlation between change in weight and change in fasting (r=0.17, p=0.49) or 2-hour glucose levels (r=0.37, p=0.14). Baseline IGFBP-1 was low (3.1 ~tg/1, SD=3.7; expected value >15), indicating long-term insulin resistance. GH (t=l.8, df=15, p=0.088), IGF-1 (t=0.58, df=15, p=0.57), and IGFBP-1 (t=l.2, df=l 5, p=0.24)were not significantly
868
Clinical Neuropsychopharmacology
changed by elozapine treatment. There was no correlation between elozapine blood levels and insulin (p=0.5), GH (p=0.7), IGF-1 (p=0.5), or IGFBP-1 (Io=0.5) levels on elozapine. Conclusions: Clozapine treatment is associated with the development of new onset abnormal glucose control in 55% of subjects within 3 months of initiation, which was not associated with weight gain. Fasting glucose levels are increased, and a prolonged hyperglycaemic peak is seen following clozapine initiation. Patients showed evidence of insulin resistance at baseline, which may be related to prior treatment with antipsychotics or the disease process seen in refractory schizophrenia. Clozapine treatment was not associated with alterations in insulin, GH, IGF, or IGFBP-1. The absence of the expected hormonal compensatory response to increased glucose levels is concerning and suggests that alterations in glucoregulation are occurring proximal to the hormonal regulation of glt~ose levels. Clozapine has been found to inhibit glucose transport into neuronal cell lines [1]. We hypothesise that clozapine impairs glucose transport into the glucose sensing neurones, thereby increasing the threshold for initiation of the hormonal homeostatic mechanisms. This mechanism would explain the rapid increase in plasma glt~ose level independent of changes in hormonal levels.
References [1] Dwyer DS, Pink&sky HB, Liu Y, Bradley RJ. Antipsychotic drugs affect glucose uptake and the expression of glucose transporters in PC12 cells. Prog Neuropsychopharmacol Biol Psychiatr 1999; 23: 69-80.
IP.3.221 Predictive factors of resistance to antidepressant treatment: results from a European multicentre study P. O s w a l d 1 , D. S o u e r y 1 , S. K a s p e r 2, Y. Lecrubier 3,
J. Zohar 4, J. Mendlewicz 1. On behalf of the Group for
the Study of Resistant Depression (GSRD). 1Department of Psychiatry, Unioersity Clinics of Brussels, Erasme Hospital, Free Unioersity of Brussels, Brussels, Belgium; 2Department of General Psychiatry, Unioersity Hospital for Psychiatry, Vienna, Austria; 3INSERM, Hdpital de la Salpgtri~re, Paris, France; 4Chaim Sheba Medical Centre, Dioision of Psychiatry, Tel Hashomer, Israel When adequately treated, up to half of all patients with major depression do not respond adequately to first-line antidepressant (AD). However, research on resistance to AD treatment has been marked with inconsistent findings, mainly due to the plethora of definitions of treatment
resistant depression (TRD) (Rush et al., 2003). During the last decade, a consensus has been raised defining TRD as the failure to respond to at least two consecutive adequate A D from different classes (Souery et al., 1999). This definition allows the investigation of clinical predicting factors of TRD. We initiated a study including seven European centres: Brussels, Sint-Truiden, Leuven, TelAviv, Paris, Vienna and Milan. A total of 996 patients with major unipolar depression having received at least one adequate AD treatment for the current episode were recruited. All patients were evaluated using the MINI (Mini International Neuropsychiatric Interview, a validated structured diagnostic interview, providing an accurate DSM-IV diagnosis (Sheehan et al., 1998). An exhaustive questionnaire was applied investigating more than 200 factors including: 1) demographic and psychosocial characteristics, 2) data on the current depressive episode, including psychiatric comorbidities, personality dimensions and somatic comorbidities, 3) personal and family history of psychiatric disorders, 4) data on current and past antidepressant and other psychotropic treatments. According to the definition of TRD, a logistic regression model was applied for which we excluded a sample of 112 patients, because they were non responder to a single and unique AD treatment, and another sample of 254 patients, because of partial missing data used for the categorization in resistant or non resistant patients. 276 unipolar patients were considered as resistant and 354 as non resistant (responder to a first or single A D or non responder to a first A D but responder to a second AD). We found that current melancholia (p=0.01), severe intensity (p=.006), current suicide risk (p<0.0001), current panic disorder (p<0.0001), current anxiety disorder (p<0.0001), a low educational level (p=0.01), personality disorder (p=0.05), current hospitalization (p=0.001), family history &bipolar disorder (p=0.05) and suicide (p=0.05), absence of response to a first antidepressant lifetime (p=0.02) and early age at onset (<16 yo, p<0.001; <18 yo, p<0.001) predict the occurrence of TRD in our unipolar sample. In a multifactorial logistic regression model, a current panic disorder, a current suicide risk and an early age at onset (<16 yo and <18 yo) were found to be the major risk factors in TRD. This is, to our knowledge, the first study investigating a large number &potential predictive factors of TRD in a multicentre European study, involving a large sample of patients with major unipolar depression. Supported by an tw~restricted grant from Lundbeck.
References [1] Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview