- Email: [email protected]
S.05.02 Bipolar Disorder: neurodevelopmental or neurodegenerative
S.05. TEM symposium – Cognitive impairment in affective disorders: a potential treatment target? (p < 0.001). In the Spontaneous Limb-Use Asymmetry Test, nicotine or levodopa given alone increase the number of contacts of the impaired limb with the cylinder (p < 0.05). Furthermore, nicotine potentiate the effects of levodopa in this test (p < 0.05). These overall results show that nicotine display anti-parkinsonian properties in the unilateral 6-OHDA-lesion rat model of Parkinson when given alone and could potentiate the effects of a low dose of levodopa. References [1] Quik, M., Parameswaran, N., McCallum, S.E., Bordia, T., Bao, S., McCormack, A., Kim, A., Tyndale, R.F., Langston, J.W., Di Monte, D.A., 2006, Chronic oral nicotine treatment protects against striatal degeneration in MPTP-treated primates. J Neurochem 98, 1866−75. [2] Visanji, N.P., O’Neill, M.J., Duty, S., 2006, Nicotine, but neither the alpha4beta2 ligand RJR2403 nor an alpha7 nAChR subtype selective agonist, protects against a partial 6-hydroxydopamine lesion of the rat median forebrain bundle. Neuropharmacology 51, 506−16.
S.04.08 Adolescent cannabinoid exposure induces sex dependent alterations in adulthood: behavioural and biochemical evidences N. Realini1 ° , D. Braida2 , S. Guidi3 , V. Capurro2 , T. Rubino1 , R. Bartesaghi3 , D. Parolaro1 . 1 University of Insubria, Dep.of Funct. and Struct. Biol., Busto Arsizio (Varese), Italy; 2 University of Milan, Dep.of Pharmacology, Milan, Italy; 3 University of Bologna, Dep.of Human and General Physiology, Bologna, Italy Marijuana is the illicit drugs most frequently used by human adolescents [1]. This work studied in rats the long-term consequences of adolescent consumption of D9 tetrahydrocannabinol (THC) on emotional and cognitive parameters. Adolescent male and female rats (35−45 PND) have been treated with increasing doses of THC for 11 days and left undisturbed until their adulthood (75 PND) when the behavioral and neurochemical assays were performed. The emotional profile was altered only in THC pretreated female rats. These animals showed a significant “behavioral despair” (forced swim test) paralleled by anhedonia (sucrose preference) and supported by biochemical parameters of depression, namely CREB alteration in the prefrontal cortex (PfCtx), hippocampus (Hippo) and nucleus accumbens (NAc). Neurocognitive functions were altered both in female and male pretreated rats, where we observed deficit in spatial memory (radial maze). To correlate memory impairment to altered neuroplasticity, level of proteins involved in synaptic plasticity was investigated in the most relevant areas for learning and memory, Hippo and PfCtx. In males we found significant reduction in pre- and post-synaptic protein expression ( ↓ 23%VAMP2, ↓ 41%PSD95) and in the astroglial marker GFAP ( ↓ 21%) in the Hippo, whereas females exhibited alterations specifically in the PfCtx ( ↓ 20%synaptophysin, ↓ 50%PSD95). Moreover THC pretreated male rats had a significant decrease in spine density and lower total dendritic length and number than vehicle group in the granule cells of the dentate gyrus. The present results suggest that cannabis consumption during adolescence may induce long term and gender dependent behavioral effects coupled with alteration in neurochemical markers and synaptic plasticity. References [1] Viveros M.P., Llorente R., Moreno E., Marco E.M., 2005. Behavioural and neuroendocrine effects of cannabinoids in critical developmental periods. Behav Pharmacol 16: 353–362.
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S.05. TEM symposium – Cognitive impairment in affective disorders: a potential treatment target? S.05.01 Cognitive impairment in affective disorders – what are the key issues? I.N. Ferrier1 ° . 1 University of Newcastle, Dept. of Psychiatry, Newcastle upon Tyne, United Kingdom In Bipolar Disorder, neurocognitive deficits occur in patients during euthymia across a number of domains. The key questions are: 1. Are impairments genuinely widespread or is there a core deficit which is expressed in different domains? 2. Do the deficits originate from a distinct regional pathology or relate to a distributed network? 3. What is the relationship between with the deficits in schizophrenia and what is the impact of a psychosis within Bipolar Disorder on this relationship? 4. The deficits worsen with number of episodes – what is the mechanism of this effect? 5. What is the relationship between impairments in Bipolar patients and those at risk of the disorder? 6. 6. What is the impact of medication? In Unipolar Depression, the key distinction is between the cognitive change found in late onset depression and that found in adult onset depression. In the former, the cognitive deficits are associated with pathology in grey and white matter and are a marker of that process and its prognosis. In adult depression, cognitive change can be found after the resolution of mood symptoms but this usually becomes a small feature in those who have made a good recovery. The above questions also relate to Unipolar Disorder but there are additional questions, eg what is the relationship between neuropsychological deficits and dysfunctional attitudes and negative cognitions. It is also not yet clear what the impact of these cognitive deficits are in functional terms and also how they impact on treatment concordance and results with psychoeducation and psychotherapy. References [1] Robinson, L.J., Thompson, J.M., Gallagher, P., Goswami, U., Young, A.H., Ferrier, I.N., Moore, P.B., 2006, A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord 93, 105–115. [2] Porter, R.J., Bourke, C., Gallagher, P., 2007, Neuropsychological impairment in major depression: its nature, origin and clinical significance. Aust NZ J Psychiatry 41, 115–128.
S.05.02 Bipolar Disorder: neurodevelopmental or neurodegenerative A. Martinez-Aran1 ° . 1 Hospital Clinic, Bipolar Disorders Program IDIBAPS CIBERSAM, Barcelona, Spain Evidence for cognitive impairment prior to illness onset in bipolar disorder is still scant. In general, data suggest that bipolar disorder is not associated with premorbid intellectual decline as would be expected in a neurodevelopmental illness. On the other hand, if neurocognitive deficits are present in unaffected family members of bipolar disorder, it is possible that these deficits are genetic in origin, suggesting possible neurodevelopmental processes. Several differently designed studies have
S164
S.05. TEM symposium – Cognitive impairment in affective disorders: a potential treatment target?
yielded inconsistent results for cognitive impairment in first degree relatives of bipolar probands [1]. However, there appears to be some evidence for minor cognitive impairments, particularly in executive function. Neurodegeneration may not be the most suitable term for the deleterious effects of repeated episodes and neurotrophic medications on cognitive performance. Although evidence for accelerated cognitive decline in bipolar disorder is still preliminary, stress- and episode-induced changes in brain regions involved in the emotional circuitry may lead to dysfunctional processing of information, which would render bipolar patients more vulnerable to subsequent environmental stressors, episodes, and drugs of abuse [2]. Anyway, the cause(s), the consequences and the potential prevention of cognitive impairments in bipolar disorder are of great contemporary interest. In this regard, there is agreement that cognitive dysfunction is highly correlated with psychosocial functioning. For this reason, cognitive impairment constitutes a potential therapeutic target, so future directions for potential cognitive enhancement strategies in bipolar disorder are required [3]. Randomized controlled trials would be helpful in order to establish their efficacy as well as the need to implement these techniques or strategies in clinical practice. References [1] Clark L, Sarna A, Goodwin GM, 2005, Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression. Am J Psychiatry 162, 1980–1982. [2] Kapczinski F, Vieta E, Andreazza AC, Frey BN, Gomes FA, Tramontina J, Kauer-Sant’anna M, Grassi-Oliveira R, Post RM, 2008, Allostatic load in bipolar disorder: Implications for pathophysiology and Treatment. Neurosci Biobehav Rev 32: 675−92. [3] Vieta E., Rosa AR, 2007, Evolving trends in the long-term treatment of bipolar disorder. World J Biol Psychiatry 8, 4−11.
S.05.03 Cognition as an endophenotype in affective disorders D.C. Glahn1 ° , M.A. Escamilla1 . 1 University of Texas Health Science, Department of Psychiatry, San Antonio, USA Although genetic influences on affective disorders are well established, localization of genes responsible for these illnesses remains elusive. Given evidence that genes predisposing to bipolar disorder may be transmitted without expression of the clinical phenotype, strategies focused on developing endophenotypes, markers of processes mediating between genotype and phenotype, have gained popularity. While several neuropsychological measures are proposed to be endophenotypes for bipolar disorder (Glahn et al., 2004), few studies have systematically assessed these tests to determine which tests are sensitive to liability for the illness. We performed 582 comprehensive neuropsychological assessments on individuals with bipolar disorder, their first and seconddegree relatives and non-related subjects. All participants were Latino individuals from extended pedigrees living in the southern United States or Central America. Families were recruited if they contained a sibling pair with bipolar disorder and at least two grandparents of Mexican or Central American origin. All of the neuropsychological tests were significantly heritable. Measures of attention, processing speed, working and declarative memory and executive functioning were impaired in probands relative to their healthy family members. Unaffected first-degree subjects were impaired on attentional and executive measures compared to unaffected second-degree family members.
These data suggest that impairments on measures of attention and executive functioning are sensitive to genetic liability for bipolar disorder and thus are candidate endophenotypes for the illness. In contrast, processing speed and memory impairments appear to be more closely linked to illness specific factors. References [1] Glahn DC, Bearden CE, Niendam TA, Escamilla MA, 2004, The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disord 6(3): 171−82.
S.05.04 Cognition in mood disorders: from neuron to therapy A. Young1 ° . 1 University of British Columbia, Institute of Mental Health, Vancouver, Canada Cognitive impairment is now well established as a core phenomenon in mood disorders, both bipolar and unipolar. Furthermore, there is robust evidence that some of this cognitive impairment is independent of medication and other potential confounds in unipolar depression and some similar evidence in bipolar disorder [1−3]. The persistence of cognitive impairment in bipolar disorder has been used to argue that this may represent either a “scar” of illness or a putative endophenotypic marker. In unipolar disorder, certain components of cognition may represent a potential marker of response. There is evidence that microstructural abnormalities of brain white matter may underlie some of the cognitive impairments found in severe mood disorders. Our studies using an MRI Diffusion Tensor Imaging approach have shown that euthymic subjects with bipolar disorder have a objective measures of abnormality of brain white matter and that this may be partially ameliorated by lithium. In another series of studies our group has examined the effects of antiglucocorticoid treatments on mood and cognition in bipolar disorder. Certain components of cognition improve after antiglucocorticoid treatment and the use of cognition as an outcome measure in proof of concept studies is being used in our ongoing studies. Our recent meta-analysis demonstrated a significant improvement in depression with antiglucocorticoid treatments. (HAM-D 50% reduction: RR 0.72, 95% CI 0.56 to 0.91). References [1] Porter RJ et al., 2003, Neurocognitive impairment in drug-free patients with major depressive disorder. Br J Psychiatry 182: 214−20. [2] Thompson JM et al., 2005, Neurocognitive impairment in euthymic patients with bipolar affective disorder. Br J Psychiatry 186: 32−40. [3] Goswami U et al., 2006, Neuropsychological dysfunction, soft neurological signs and social disability in euthymic patients with bipolar disorder. Br J Psychiatry 188: 366−73.
S.05.05 Future prospects on the biological and treatment correlates of cognitive deficits in affective disorders G.S. Malhi1 ° , J. Lagopoulos1 . 1 University of Sydney, CADE Clinic Psychological Medicine, Sydney, Australia It has long been recognised that there are discernible neurocognitive deficits in depression and bipolar disorder that impact upon occupational and social functioning. In recent years the focus has shifted from unipolar depression to bipolar disorder and clinical
S.04.08 Adolescent cannabinoid exposure induces sex dependent alterations in adulthood: behavioural and biochemical evidences N. Realini1 ° , D. Braida2 , S. Guidi3 , V. Capurro2 , T. Rubino1 , R. Bartesaghi3 , D. Parolaro1 . 1 University of Insubria, Dep.of Funct. and Struct. Biol., Busto Arsizio (Varese), Italy; 2 University of Milan, Dep.of Pharmacology, Milan, Italy; 3 University of Bologna, Dep.of Human and General Physiology, Bologna, Italy Marijuana is the illicit drugs most frequently used by human adolescents [1]. This work studied in rats the long-term consequences of adolescent consumption of D9 tetrahydrocannabinol (THC) on emotional and cognitive parameters. Adolescent male and female rats (35−45 PND) have been treated with increasing doses of THC for 11 days and left undisturbed until their adulthood (75 PND) when the behavioral and neurochemical assays were performed. The emotional profile was altered only in THC pretreated female rats. These animals showed a significant “behavioral despair” (forced swim test) paralleled by anhedonia (sucrose preference) and supported by biochemical parameters of depression, namely CREB alteration in the prefrontal cortex (PfCtx), hippocampus (Hippo) and nucleus accumbens (NAc). Neurocognitive functions were altered both in female and male pretreated rats, where we observed deficit in spatial memory (radial maze). To correlate memory impairment to altered neuroplasticity, level of proteins involved in synaptic plasticity was investigated in the most relevant areas for learning and memory, Hippo and PfCtx. In males we found significant reduction in pre- and post-synaptic protein expression ( ↓ 23%VAMP2, ↓ 41%PSD95) and in the astroglial marker GFAP ( ↓ 21%) in the Hippo, whereas females exhibited alterations specifically in the PfCtx ( ↓ 20%synaptophysin, ↓ 50%PSD95). Moreover THC pretreated male rats had a significant decrease in spine density and lower total dendritic length and number than vehicle group in the granule cells of the dentate gyrus. The present results suggest that cannabis consumption during adolescence may induce long term and gender dependent behavioral effects coupled with alteration in neurochemical markers and synaptic plasticity. References [1] Viveros M.P., Llorente R., Moreno E., Marco E.M., 2005. Behavioural and neuroendocrine effects of cannabinoids in critical developmental periods. Behav Pharmacol 16: 353–362.
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S.05. TEM symposium – Cognitive impairment in affective disorders: a potential treatment target? S.05.01 Cognitive impairment in affective disorders – what are the key issues? I.N. Ferrier1 ° . 1 University of Newcastle, Dept. of Psychiatry, Newcastle upon Tyne, United Kingdom In Bipolar Disorder, neurocognitive deficits occur in patients during euthymia across a number of domains. The key questions are: 1. Are impairments genuinely widespread or is there a core deficit which is expressed in different domains? 2. Do the deficits originate from a distinct regional pathology or relate to a distributed network? 3. What is the relationship between with the deficits in schizophrenia and what is the impact of a psychosis within Bipolar Disorder on this relationship? 4. The deficits worsen with number of episodes – what is the mechanism of this effect? 5. What is the relationship between impairments in Bipolar patients and those at risk of the disorder? 6. 6. What is the impact of medication? In Unipolar Depression, the key distinction is between the cognitive change found in late onset depression and that found in adult onset depression. In the former, the cognitive deficits are associated with pathology in grey and white matter and are a marker of that process and its prognosis. In adult depression, cognitive change can be found after the resolution of mood symptoms but this usually becomes a small feature in those who have made a good recovery. The above questions also relate to Unipolar Disorder but there are additional questions, eg what is the relationship between neuropsychological deficits and dysfunctional attitudes and negative cognitions. It is also not yet clear what the impact of these cognitive deficits are in functional terms and also how they impact on treatment concordance and results with psychoeducation and psychotherapy. References [1] Robinson, L.J., Thompson, J.M., Gallagher, P., Goswami, U., Young, A.H., Ferrier, I.N., Moore, P.B., 2006, A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord 93, 105–115. [2] Porter, R.J., Bourke, C., Gallagher, P., 2007, Neuropsychological impairment in major depression: its nature, origin and clinical significance. Aust NZ J Psychiatry 41, 115–128.
S.05.02 Bipolar Disorder: neurodevelopmental or neurodegenerative A. Martinez-Aran1 ° . 1 Hospital Clinic, Bipolar Disorders Program IDIBAPS CIBERSAM, Barcelona, Spain Evidence for cognitive impairment prior to illness onset in bipolar disorder is still scant. In general, data suggest that bipolar disorder is not associated with premorbid intellectual decline as would be expected in a neurodevelopmental illness. On the other hand, if neurocognitive deficits are present in unaffected family members of bipolar disorder, it is possible that these deficits are genetic in origin, suggesting possible neurodevelopmental processes. Several differently designed studies have
S164
S.05. TEM symposium – Cognitive impairment in affective disorders: a potential treatment target?
yielded inconsistent results for cognitive impairment in first degree relatives of bipolar probands [1]. However, there appears to be some evidence for minor cognitive impairments, particularly in executive function. Neurodegeneration may not be the most suitable term for the deleterious effects of repeated episodes and neurotrophic medications on cognitive performance. Although evidence for accelerated cognitive decline in bipolar disorder is still preliminary, stress- and episode-induced changes in brain regions involved in the emotional circuitry may lead to dysfunctional processing of information, which would render bipolar patients more vulnerable to subsequent environmental stressors, episodes, and drugs of abuse [2]. Anyway, the cause(s), the consequences and the potential prevention of cognitive impairments in bipolar disorder are of great contemporary interest. In this regard, there is agreement that cognitive dysfunction is highly correlated with psychosocial functioning. For this reason, cognitive impairment constitutes a potential therapeutic target, so future directions for potential cognitive enhancement strategies in bipolar disorder are required [3]. Randomized controlled trials would be helpful in order to establish their efficacy as well as the need to implement these techniques or strategies in clinical practice. References [1] Clark L, Sarna A, Goodwin GM, 2005, Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression. Am J Psychiatry 162, 1980–1982. [2] Kapczinski F, Vieta E, Andreazza AC, Frey BN, Gomes FA, Tramontina J, Kauer-Sant’anna M, Grassi-Oliveira R, Post RM, 2008, Allostatic load in bipolar disorder: Implications for pathophysiology and Treatment. Neurosci Biobehav Rev 32: 675−92. [3] Vieta E., Rosa AR, 2007, Evolving trends in the long-term treatment of bipolar disorder. World J Biol Psychiatry 8, 4−11.
S.05.03 Cognition as an endophenotype in affective disorders D.C. Glahn1 ° , M.A. Escamilla1 . 1 University of Texas Health Science, Department of Psychiatry, San Antonio, USA Although genetic influences on affective disorders are well established, localization of genes responsible for these illnesses remains elusive. Given evidence that genes predisposing to bipolar disorder may be transmitted without expression of the clinical phenotype, strategies focused on developing endophenotypes, markers of processes mediating between genotype and phenotype, have gained popularity. While several neuropsychological measures are proposed to be endophenotypes for bipolar disorder (Glahn et al., 2004), few studies have systematically assessed these tests to determine which tests are sensitive to liability for the illness. We performed 582 comprehensive neuropsychological assessments on individuals with bipolar disorder, their first and seconddegree relatives and non-related subjects. All participants were Latino individuals from extended pedigrees living in the southern United States or Central America. Families were recruited if they contained a sibling pair with bipolar disorder and at least two grandparents of Mexican or Central American origin. All of the neuropsychological tests were significantly heritable. Measures of attention, processing speed, working and declarative memory and executive functioning were impaired in probands relative to their healthy family members. Unaffected first-degree subjects were impaired on attentional and executive measures compared to unaffected second-degree family members.
These data suggest that impairments on measures of attention and executive functioning are sensitive to genetic liability for bipolar disorder and thus are candidate endophenotypes for the illness. In contrast, processing speed and memory impairments appear to be more closely linked to illness specific factors. References [1] Glahn DC, Bearden CE, Niendam TA, Escamilla MA, 2004, The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disord 6(3): 171−82.
S.05.04 Cognition in mood disorders: from neuron to therapy A. Young1 ° . 1 University of British Columbia, Institute of Mental Health, Vancouver, Canada Cognitive impairment is now well established as a core phenomenon in mood disorders, both bipolar and unipolar. Furthermore, there is robust evidence that some of this cognitive impairment is independent of medication and other potential confounds in unipolar depression and some similar evidence in bipolar disorder [1−3]. The persistence of cognitive impairment in bipolar disorder has been used to argue that this may represent either a “scar” of illness or a putative endophenotypic marker. In unipolar disorder, certain components of cognition may represent a potential marker of response. There is evidence that microstructural abnormalities of brain white matter may underlie some of the cognitive impairments found in severe mood disorders. Our studies using an MRI Diffusion Tensor Imaging approach have shown that euthymic subjects with bipolar disorder have a objective measures of abnormality of brain white matter and that this may be partially ameliorated by lithium. In another series of studies our group has examined the effects of antiglucocorticoid treatments on mood and cognition in bipolar disorder. Certain components of cognition improve after antiglucocorticoid treatment and the use of cognition as an outcome measure in proof of concept studies is being used in our ongoing studies. Our recent meta-analysis demonstrated a significant improvement in depression with antiglucocorticoid treatments. (HAM-D 50% reduction: RR 0.72, 95% CI 0.56 to 0.91). References [1] Porter RJ et al., 2003, Neurocognitive impairment in drug-free patients with major depressive disorder. Br J Psychiatry 182: 214−20. [2] Thompson JM et al., 2005, Neurocognitive impairment in euthymic patients with bipolar affective disorder. Br J Psychiatry 186: 32−40. [3] Goswami U et al., 2006, Neuropsychological dysfunction, soft neurological signs and social disability in euthymic patients with bipolar disorder. Br J Psychiatry 188: 366−73.
S.05.05 Future prospects on the biological and treatment correlates of cognitive deficits in affective disorders G.S. Malhi1 ° , J. Lagopoulos1 . 1 University of Sydney, CADE Clinic Psychological Medicine, Sydney, Australia It has long been recognised that there are discernible neurocognitive deficits in depression and bipolar disorder that impact upon occupational and social functioning. In recent years the focus has shifted from unipolar depression to bipolar disorder and clinical