- Email: [email protected]
Regression of cognitive impairment in depression
S380
P.2.b. Mood disorders and treatment − Affective disorders (clinical)
(FST). We systematically administered pharmacological treatment thirty minutes prior to the fifth consecutive day of testing in the FST; mice were treated with saline, ketamine, citalopram, 8OH-DPAT, or 8OH-DPAT/SB269970 combination. Finally, we conducted biochemical analyses of the 2C19TG HC by western blot, HPLC, and qPCR. Results: Healthy subjects carrying CYP2C19*2/2 genotype demonstrated bilateral HC volume enlargement in both studied cohorts. CYP2C19*2/2 African-Americans exhibited less depressive symptoms (24.61% (2.05 points) Beck’s Depression Inventory score reduction, p = 0.020) and MDD prevalence (27.84% prevalence reduction, p = 0.039). Conversely, the CYP2C19*17 allele was associated with higher suicidality in the suicide attempter cohort (25.69% (1.36 points) Beck’s Suicide Intent ScaleObjective Circumstances score increase). 2C19TG mice showed higher stress-sensitivity, impaired HC Bdnf homeostasis in stress and more despair-like behavior in the forced swim test (FST). Ketamine and citalopram reduced the immobility time in both 2C19TG and control mice; however, when exposed to citalopram prior to the FST, the reduction in the time spent immobile was significantly increased in 2C19TG mice compared to controls. Selective serotonin (5-HT)1A receptor activation was sufficient to mimic the citalopram effect in the FST; the time spent immobile was reduced in the 2C19TG more than in control mice after 8OHDPAT treatment. Conversely, metabolic (5-Hydroxyindoleacetic acid/5-HT) turnover of 5-HT and Htr7 expression was reduced and ERK phosphorylation was increased in the HC of the 2C19TG mutants. Conclusions: Our translational study indicates that an increase in CYP2C19 expression can cause MDD-related symptoms in humans and depressive-like phenotype in mice. Preclinical findings indicate that CYP2C19 expression impaired 5-HT and BDNF homeostasis in the HC and suggests that a decrease in HC 5-HT1AGi signaling is mediating at least some of the observed 2C19TG mouse phenotypes. References [1] Persson, A., Sim, S.C., Virding, S., Onishchenko, N., Schulte, G., Ingelman-Sundberg, M., 2014. Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Mol Psychiatry 19(6):733−41. [2] Ingelman-Sundberg, M., Sim, S.C., Gomez, A., Rodriguez-Antona, C., 2007. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 116(5):496–526. [3] Sim, S.C., Nordin, L., Andersson, T.M., Virding, S., Olsson, M., Pedersen, N.L., Ingelman-Sundberg, M., 2010. Association between CYP2C19 polymorphism and depressive symptoms. Am J Med Genet B Neuropsychiatr Genet 153(6):1160−6.
P.2.b. Mood disorders and treatment − Affective disorders (clinical) P.2.b.001 Regression of cognitive impairment in depression A. Chistol1 ° of
1 Mental
Health Center, Chisinau, Moldova- Rep.
Background: Cognitive impairment has been attributed to depressive symptoms and a lot of studies have involved patients during the acute phase of depression. However, in the last decade it was widely reported that cognitive dysfunction remains unresolved even after remission of depressive symptoms [1]. It is now
commonly accepted that depression is associated with a number of deficits in learning and memory [2]. Recent studies reveal that up to 90% of patients with depression have at least one cognitive disorder symptom remaining after the treatment [3]. Aims: We aim to examine the status of cognitive deficits in depression by estimating the cognitive impairment after treatment, as well as identify if intensity of depressive symptoms correlates with the intensity of cognitive problems. Methods: The study included 40 patients suffering from depressive symptoms, which were observed during at least 6 months prior to the study. Psychiatric examination for depressive disorder was based on International Statistical Classification of Disease 10th version. The patients underwent the Montreal Cognitive Assessment, the Self-Rating Depression Scale, the Hamilton Depression Scale and the Hamilton Anxiety Scale at the beginning of the treatment and after 3 and 6 months of therapy. During this period they received pharmacotherapy based on Selective Serotonin Reuptake Inhibitors and Serotonin-norepinephrine reuptake inhibitors in therapeutic doses. The data was analyzed with one-way ANOVA for repeated measures followed by contrasts. Additionally, we examined the relationship between severities of cognitive disorders and number of depressive episodes experienced by calculating Spearmen’s correlation. Results: Our data shows that cognitive impairment is not reduced with time or after antidepressant treatment. No significant difference was found between cognitive assessment on 1, 3 and 6 months. It demonstrates that cognitive dysfunction persists inside the depressive episodes, between them and in remission. However, a significant effect was found for Hamilton Anxiety Scale [F(2,38) = 45.4, p < 0.0001] and for Hamilton Depression Scale [F(2,38) = 12.29, p < 0.0001]. It demonstrates that both depressive symptoms and anxiety improved during treatment. Contrasts test further revealed a significant difference between depressive symptoms tested on 1 month and 3 month [F(1,39) = 224.01, p < 0.0001]. Likewise a significant difference between depressive symptoms on the 3rd and on the 6th month [F(1,39) = 375.11, p < 0.0001]. We trace the similar phenomenon in anxiety symptoms: the contrast test revealed that anxiety tested on the 1st month is significantly higher than anxiety tested on the 2nd month [F(1,39) = 266.09, p < 0.0001] and anxiety tested on the 2nd month is higher than anxiety tested on the 3rd month [F(1,39) = 1100.63, p < 0.0001]. It suggests that cognitive impairment remains without positive dynamics while the depressive symptom improves under treatment. The severity of depressive symptoms did not predict the severity of cognitive dysfunction. In the same time cognitive disorder did not correlate with the severity of depression, but it correlated with the number of episodes experienced (Rs = −0.769, p < 0.0001). References [1] Papazacharias A., Nardini M., 2012. The relationship between depression and cognitive deficits. Psychiatria Danubina 24, Suppl.1, 179–182. [2] Austin M.P., Mitchell P., Goodwin G.M., 2001. Cognitive deficits in depression: possible implications for functional neuropathology. The British Journal Of Psychiatry 178, 200–206. [3] Boeker H., Schulze J., Richter A., Nikisch G., Schuepbach D., Grimm S. 2012. Sustained cognitive impairments after clinical recovery of severe depression. The Journal Of Nervous And Mental Disease 200(9):773–776.
P.2.b. Mood disorders and treatment − Affective disorders (clinical)
(FST). We systematically administered pharmacological treatment thirty minutes prior to the fifth consecutive day of testing in the FST; mice were treated with saline, ketamine, citalopram, 8OH-DPAT, or 8OH-DPAT/SB269970 combination. Finally, we conducted biochemical analyses of the 2C19TG HC by western blot, HPLC, and qPCR. Results: Healthy subjects carrying CYP2C19*2/2 genotype demonstrated bilateral HC volume enlargement in both studied cohorts. CYP2C19*2/2 African-Americans exhibited less depressive symptoms (24.61% (2.05 points) Beck’s Depression Inventory score reduction, p = 0.020) and MDD prevalence (27.84% prevalence reduction, p = 0.039). Conversely, the CYP2C19*17 allele was associated with higher suicidality in the suicide attempter cohort (25.69% (1.36 points) Beck’s Suicide Intent ScaleObjective Circumstances score increase). 2C19TG mice showed higher stress-sensitivity, impaired HC Bdnf homeostasis in stress and more despair-like behavior in the forced swim test (FST). Ketamine and citalopram reduced the immobility time in both 2C19TG and control mice; however, when exposed to citalopram prior to the FST, the reduction in the time spent immobile was significantly increased in 2C19TG mice compared to controls. Selective serotonin (5-HT)1A receptor activation was sufficient to mimic the citalopram effect in the FST; the time spent immobile was reduced in the 2C19TG more than in control mice after 8OHDPAT treatment. Conversely, metabolic (5-Hydroxyindoleacetic acid/5-HT) turnover of 5-HT and Htr7 expression was reduced and ERK phosphorylation was increased in the HC of the 2C19TG mutants. Conclusions: Our translational study indicates that an increase in CYP2C19 expression can cause MDD-related symptoms in humans and depressive-like phenotype in mice. Preclinical findings indicate that CYP2C19 expression impaired 5-HT and BDNF homeostasis in the HC and suggests that a decrease in HC 5-HT1AGi signaling is mediating at least some of the observed 2C19TG mouse phenotypes. References [1] Persson, A., Sim, S.C., Virding, S., Onishchenko, N., Schulte, G., Ingelman-Sundberg, M., 2014. Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Mol Psychiatry 19(6):733−41. [2] Ingelman-Sundberg, M., Sim, S.C., Gomez, A., Rodriguez-Antona, C., 2007. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 116(5):496–526. [3] Sim, S.C., Nordin, L., Andersson, T.M., Virding, S., Olsson, M., Pedersen, N.L., Ingelman-Sundberg, M., 2010. Association between CYP2C19 polymorphism and depressive symptoms. Am J Med Genet B Neuropsychiatr Genet 153(6):1160−6.
P.2.b. Mood disorders and treatment − Affective disorders (clinical) P.2.b.001 Regression of cognitive impairment in depression A. Chistol1 ° of
1 Mental
Health Center, Chisinau, Moldova- Rep.
Background: Cognitive impairment has been attributed to depressive symptoms and a lot of studies have involved patients during the acute phase of depression. However, in the last decade it was widely reported that cognitive dysfunction remains unresolved even after remission of depressive symptoms [1]. It is now
commonly accepted that depression is associated with a number of deficits in learning and memory [2]. Recent studies reveal that up to 90% of patients with depression have at least one cognitive disorder symptom remaining after the treatment [3]. Aims: We aim to examine the status of cognitive deficits in depression by estimating the cognitive impairment after treatment, as well as identify if intensity of depressive symptoms correlates with the intensity of cognitive problems. Methods: The study included 40 patients suffering from depressive symptoms, which were observed during at least 6 months prior to the study. Psychiatric examination for depressive disorder was based on International Statistical Classification of Disease 10th version. The patients underwent the Montreal Cognitive Assessment, the Self-Rating Depression Scale, the Hamilton Depression Scale and the Hamilton Anxiety Scale at the beginning of the treatment and after 3 and 6 months of therapy. During this period they received pharmacotherapy based on Selective Serotonin Reuptake Inhibitors and Serotonin-norepinephrine reuptake inhibitors in therapeutic doses. The data was analyzed with one-way ANOVA for repeated measures followed by contrasts. Additionally, we examined the relationship between severities of cognitive disorders and number of depressive episodes experienced by calculating Spearmen’s correlation. Results: Our data shows that cognitive impairment is not reduced with time or after antidepressant treatment. No significant difference was found between cognitive assessment on 1, 3 and 6 months. It demonstrates that cognitive dysfunction persists inside the depressive episodes, between them and in remission. However, a significant effect was found for Hamilton Anxiety Scale [F(2,38) = 45.4, p < 0.0001] and for Hamilton Depression Scale [F(2,38) = 12.29, p < 0.0001]. It demonstrates that both depressive symptoms and anxiety improved during treatment. Contrasts test further revealed a significant difference between depressive symptoms tested on 1 month and 3 month [F(1,39) = 224.01, p < 0.0001]. Likewise a significant difference between depressive symptoms on the 3rd and on the 6th month [F(1,39) = 375.11, p < 0.0001]. We trace the similar phenomenon in anxiety symptoms: the contrast test revealed that anxiety tested on the 1st month is significantly higher than anxiety tested on the 2nd month [F(1,39) = 266.09, p < 0.0001] and anxiety tested on the 2nd month is higher than anxiety tested on the 3rd month [F(1,39) = 1100.63, p < 0.0001]. It suggests that cognitive impairment remains without positive dynamics while the depressive symptom improves under treatment. The severity of depressive symptoms did not predict the severity of cognitive dysfunction. In the same time cognitive disorder did not correlate with the severity of depression, but it correlated with the number of episodes experienced (Rs = −0.769, p < 0.0001). References [1] Papazacharias A., Nardini M., 2012. The relationship between depression and cognitive deficits. Psychiatria Danubina 24, Suppl.1, 179–182. [2] Austin M.P., Mitchell P., Goodwin G.M., 2001. Cognitive deficits in depression: possible implications for functional neuropathology. The British Journal Of Psychiatry 178, 200–206. [3] Boeker H., Schulze J., Richter A., Nikisch G., Schuepbach D., Grimm S. 2012. Sustained cognitive impairments after clinical recovery of severe depression. The Journal Of Nervous And Mental Disease 200(9):773–776.