Clinical care for major depressive disorder (MDD) would be greatly improved if we had reliable clinical predictors of individual antidepressant treatment outcome. While, at the present time, no biomarkers have sufficiently proven utility to be ready for clinical application, several neuroimaging modalities have shown promise for such development. Attempts to combine the recently developed modality of resting-state functional Magnetic Resonance Imaging (rs-fMRI) with pharmacological challenges to explore the impact of antidepressants on resting-state brain connectivity have just begun (McCabe et al., 2011a, McCabe et al., 2011b). The aim of the current study was to investigate the effects of a single dose of the SSRI (selective serotonin reuptake inhibitor) escitalopram on resting-state functional connectivity in health.

Objective: To determine whether genotype at the catechol-O-methyltransferase rs4680, dopamine D2 receptor rs1800497, serotonin receptor 1A rs6295 or serotonin transporter 5-HTTLPR single nucleotide polymorphisms is associated with response to citalopram and escitalopram treatment in patients with major depressive disorder and generalized anxiety disorder. Methods: Twenty one patients with depression or anxiety who were treated with citalopram or escitalopram for greater than one year, and who stopped the medication for a period of time during which their symptoms returned, and upon re-commencing the medication their symptoms were again reduced, were classified as responders. Patients were assessed using the Sheehan Disability Scale and the Quick Inventory of Depressive Symptomology- self report. The control group consisted of 146 healthy participants. Genotype was determined at each of the candidate genes studied: catechol-O-methyltransferase, dopamine D2 receptor, serotonin receptor 1A and serotonin transporter. Chi squared tests were used to compare genotypic and allele frequencies between responders and controls. Results: There was no significant difference in genotypic or allele frequencies between responders and controls at each of the genes analyzed. Conclusions: This pilot study suggests that genotype at the catechol-O-methyltransferase, dopamine D2 receptor, serotonin receptor 1A and serotonin transporter genes is not associated with response to citalopram and escitalopram treatment in patients with depression and anxiety. A larger sample size, along with a genome-wide scan are needed to identify genetic variants that predict medication response in future patients. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-08-31 12:26:21.402

Hyponatriämie, definiert als Serum-Natrium < 135 mmol/l, ist ein potentiell lebensbedrohender Zustand und wird häufig bei älteren und psychiatrischen Patienten beobachtet. In den letzten Jahren wurden viele Case reports über SSRI- und SNRI- induzierte Hyponatriämien publiziert. Kardiale Veränderungen, insbesondere eine verlängerte QT-Zeit oder erhöhte Herzfrequenz, werden auch als häufig beobachtete Nebenwirkungen unter Therapie mit Antidepressiva beschrieben. Dies konnte bislang insbesondere während der Einnahme von trizyklischen Antidepressiva beobachtet werden. Oft kann der beobachtete Effekt in Zusammenhang mit der verabreichten Dosis gebracht werden. Bei der SSRI- bzw. SNRI-induzierten Hyponatriämie konnte dies bislang nicht gezeigt werden. In der Literatur lassen sich im Allgemeinen kaum Studien finden, die einen Zusammenhang der Serumkonzentration von SSRI und SNRI auf potentiell auftretende Nebenwirkungen untersucht haben. Ziel der vorliegenden Studie war zu zeigen, ob höhere Serumkonzentrationen von Citalopram, Escitalopram, Sertralin, Venlafaxin oder Duloxetin häufiger zu Hyponatriämien bzw. Verlängerungen der QT-Zeit führen. / Hyponatremia, defined as a serum sodium below 135 mmol/L, is a potentially life-threatening condition and was shown to be more frequent in elderly and psychiatric patients. In the last years numerous case reports on SSRI- and SNRI-induced hyponatremia were published indicating a higher incidence than previously thought. Cardiac side effects, especially QT-interval prolongation, are also reported as a common side effect under therapy with antidepressants in general. While QT-interval prolongation seems to be dose-dependent, SSRI-induced hyponatremia was shown not to correlate with dose. There were hardly studies, who investigate a correlation between plasma levels of SSRI and SNRI and potentially occuring side effects. Aim of this study was to show, if there is a higher incidence of hyponatremia and QT-interval prolongation under increasing plasma levels of Citalopram, Escitalopram, Sertralin, Venlafaxin and Duloxetin.

Diese retrospektive, naturalistische Studie beschäftigte sich mit dem Therapeutischen Drug Monitoring von Kindern und Jugendlichen unter Psychopharmakotherapie mit Escitalopram und Mirtazapin. Die Datenauswertung erfolgte anhand von klinischen Routinedaten aus dem TDM-Service des Speziallabors für TDM des Zentrums für psychische Gesundheit des Universitätsklinikums Würzburg. In der Studie wurden die Zusammenhänge zwischen Dosis, Serumkonzentration und positiver bzw. negativer klinischer Effekte, auch im Hinblick auf mögliche Einflussfaktoren wie Geschlecht, Alter, BMI-Status, Komedikation und Raucherstatus, untersucht. Ein weiteres Ziel der Arbeit war, Hinweise für die Definition eines altersspezifischen therapeutischen Referenzbereiches (Diagnoseübergreifend und Depressions-spezifisch) für Kinder und Jugendliche beider Medikamente zu gewinnen. Hierfür wurden für Escitalopram 41 Patienten im Alter zwischen elf und 18 Jahren und für Mirtazapin 23 Patienten im Alter von sechs bis 18 Jahren eingeschlossen und Daten zur Demographie, Serumkonzentrationsbestimmungen im Steady State, Schwere der Erkrankung (CGI-S), Therapieeffektivität (CGI-I) und Nebenwirkungen (UKU-Skala) ausgewertet. Escitalopram: Die mittlere Tagesdosis betrug 14,8 mg, wobei die Serumkonzentrationen mit einer mittleren Konzentration von 32,2 ng/ml (SD= 26,6 ng/ml) zwischen sechs und 109 ng/ml schwankten. Bei 63,4 % der Patienten lag die ermittelte Serumkonzentration in dem für Erwachsene definierten therapeutischen Referenzbereich (15-80 ng/ml). Zwischen der Tagesdosis und der Serumkonzentration ergab sich eine auf dem 1 %-Niveau signifikante positive lineare Beziehung (rs= 0,46; p= 0,003). 65,9 % der Patienten respondierten seit Behandlungsbeginn. Zwischen der Serumkonzentration und dem therapeutischen Effekt (rs= 0,193; p= 0,282) und zwischen der Serumkonzentration und den Nebenwirkungen (r= 0,127; p= 0,467) konnte jeweils kein signifikanter Zusammenhang gefunden werden. Die Nebenwirkungsrate lag bei 25,7 %, wobei am häufigsten Spannung und innere Unruhe dokumentiert wurde. Mit der Idee, die Definition für den vorläufigen therapeutischen Referenzbereich sowohl der Konsensus-Leitlinie der AGNP (Hiemke et al., 2018) als auch von Hiemke (2019) zu berücksichtigen, wird als vorläufiger therapeutischer Referenzbereich für Escitalopram für Kinder und Jugendliche mit Depression eine untere Grenze zwischen 10 ng/ml bis 15 ng/ml und eine obere Grenze von 50 ng/ml vorgeschlagen. Dieser Bereich liegt niedriger als der für erwachsene Patienten definierte Bereich für Escitalopram von 15 bis 80 ng/ml. Mirtazapin: Die mittlere Tagesdosis betrug 28,6 mg, wobei die Serumkonzentrationen mit einer mittleren Konzentration von 40,8 ng/ml (SD= 28,1 ng/ml) zwischen 13 und 130 ng/ml schwankten. Für 52,2 % der Patienten lag die Serumkonzentration in dem für Erwachsene definierten therapeutischen Referenzbereich (30-80 ng/ml). Zwischen der Tagesdosis und der Serumkonzentration ergab sich eine auf dem 1 %-Niveau signifikante positive Korrelation (rs= 0,655; p= 0,001). Hinsichtlich des Therapieeffektes respondierten 52,2 % der Patienten seit Behandlungsbeginn. Zwischen der Serumkonzentration und dem therapeutischen Effekt ergab sich ein auf dem 5 %-Niveau signifikanter positiver Zusammenhang (rs= 0,534; p= 0,015). Zwischen der Serumkonzentration und den Nebenwirkungen konnte kein signifikanter Zusammenhang gefunden werden (r= 0,240; p= 0,282). Die Nebenwirkungsrate lag bei 30,4 %, wobei Schläfrigkeit und Sedierung am häufigsten berichtet wurden. Als vorläufiger therapeutischer Referenzbereich für Mirtazapin für Kinder und Jugendliche mit Depression wird eine untere Grenze zwischen 15 ng/ml bis 20 ng/ml und eine obere Grenze von 50 ng/ml vorgeschlagen. Dieser Bereich liegt niedriger als der für erwachsene Patienten definierte Bereich für Mirtazapin von 30 bis 80 ng/ml. Die Limitationen der vorliegenden naturalistischen Studie beachtend, sollten die Ergebnisse mit Vorsicht interpretiert und anhand einer größeren Stichprobe unter kontrollierteren Bedingungen überprüft werden. / This retrospective, naturalistic study focussed on the therapeutic drug monitoring of children and adolescents treated with escitalopram and mirtazapine. The data analysis was based on routine clinical data from the TDM service of the special laboratory for TDM at the Centre for Mental Health at the University Hospital of Würzburg. The study analysed the correlations between dose, serum concentration and positive or negative clinical effects, also with regard to possible influencing factors such as gender, age, BMI status, comedication and smoking status. A further aim of the study was to obtain indications for the definition of an age-specific therapeutic reference range (cross-diagnostic and depression-specific) for children and adolescents of both drugs. For this purpose, 41 patients aged between eleven and 18 years were included for escitalopram and 23 patients aged between six and 18 years for mirtazapine, and data on demographics, serum concentration determinations in steady state, severity of illness (CGI-S), treatment efficacy (CGI-I) and side effects (UKU scale) were analysed. Escitalopram: The mean daily dose was 14.8 mg, with serum concentrations varying between six and 109 ng/ml with a mean concentration of 32.2 ng/ml (SD= 26.6 ng/ml). In 63.4 % of patients, the serum concentration determined was within the therapeutic reference range defined for adults (15-80 ng/ml). There was a significant positive linear relationship between the daily dose and the serum concentration (rs= 0.46; p= 0.003). 65.9 % of patients responded since the start of treatment. No significant correlation was found between the serum concentration and the therapeutic effect (rs= 0.193; p= 0.282) and between the serum concentration and the side effects (r= 0.127; p= 0.467). The side effect rate was 25.7 %, with tension and restlessness being the most frequently documented. With the idea of taking into account the definition for the preliminary therapeutic reference range of both the AGNP consensus guideline (Hiemke et al., 2018) and Hiemke (2019), a lower limit of between 10 ng/ml and 15 ng/ml and an upper limit of 50 ng/ml is proposed as the preliminary therapeutic reference range for escitalopram for children and adolescents with depression. This range is lower than the range for escitalopram defined for adult patients of 15 to 80 ng/ml. Mirtazapine: The mean daily dose was 28.6 mg, with serum concentrations varying between 13 and 130 ng/ml with a mean concentration of 40.8 ng/ml (SD= 28.1 ng/ml). For 52.2 % of patients, the serum concentration was within the therapeutic reference range defined for adults (30-80 ng/ml). There was a significant positive correlation between the daily dose and the serum concentration (rs= 0.655; p= 0.001). With regard to the treatment effect, 52.2 % of patients responded since the start of treatment. There was a significant positive correlation between the serum concentration and the therapeutic effect (rs= 0.534; p= 0.015). No significant correlation was found between the serum concentration and the side effects (r= 0.240; p= 0.282). The adverse event rate was 30.4%, with drowsiness and sedation being the most frequently reported. A lower limit of 15 ng/ml to 20 ng/ml and an upper limit of 50 ng/ml is proposed as a preliminary therapeutic reference range for mirtazapine for children and adolescents with depression. This range is lower than the range for mirtazapine defined for adult patients of 30 to 80 ng/ml. Bearing in mind the limitations of the present naturalistic study, the results should be interpreted with caution and verified using a larger sample size under more controlled conditions.

ALVES NETO, W.C. Efeitos do escitalopram sobre a identificação de expressões faciais. Ribeirão Preto, SP: Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo; 2008. Os inibidores seletivos da recaptura de serotonina (ISRS) têm sido utilizados com sucesso para o tratamento de diversas patologias psiquiátricas. Sua eficácia clínica é atribuída a uma potencialização da neurotransmissão serotoninérgica, mas pouco ainda é conhecido sobre os mecanismos neuropsicológicos envolvidos nesse processo. Várias evidências sugerem que a serotonina estaria envolvida, entre outras funções, na regulação do comportamento social, nos processos de aprendizagem e memória e no processamento de emoções. O reconhecimento de expressões faciais de emoções básicas representa um valioso paradigma para o estudo do processamento de emoções, pois são estímulos condensados, uniformes e de grande relevância para o funcionamento social. O objetivo do estudo foi avaliar os efeitos da administração aguda e por via oral do escitalopram, um ISRS, no reconhecimento de expressões faciais de emoções básicas. Uma dose oral de 10 mg de escitalopram foi administrada a doze voluntários saudáveis do sexo masculino, em modelo duplo-cego, controlado por placebo, em delineamento cruzado, ordem randômica, 3 horas antes de realizarem a tarefa de reconhecimento de expressões faciais, com seis emoções básicas raiva, medo, tristeza, asco, alegria e surpresa mais a expressão neutra. As faces foram digitalmente modificadas de forma a criar um gradiente de intensidade entre 10 e 100% de cada emoção, com incrementos sucessivos de 10%. Foram registrados os estados subjetivos de humor e ansiedade ao longo da tarefa e o desempenho foi avaliado pela medida de acurácia (número de acertos sobre o total de estímulos apresentados). De forma geral, o escitalopram interferiu no reconhecimento de todas as expressões faciais, à exceção de medo. Especificamente, facilitou a identificação das faces de tristeza e prejudicou o reconhecimento de alegria. Quando considerado o gênero das faces, esse efeito foi observado para as faces masculinas, enquanto que para as faces femininas o escitalopram não interferiu com o reconhecimento de tristeza e aumentou o de alegria. Além disso, aumentou o reconhecimento das faces de raiva e asco quando administrado na segunda sessão e prejudicou a identificação das faces de surpresa nas intensidades intermediárias de gradação. Também apresentou um efeito positivo global sobre o desempenho na tarefa quando administrado na segunda sessão. Os resultados sugerem uma modulação serotoninérgica sobre o reconhecimento de expressões faciais emocionais e sobre a evocação de material previamente aprendido. / ALVES NETO, W.C. Effects of escitalopram on the processing of emotional faces. Ribeirão Preto, SP: Faculty of Medicine of Ribeirão Preto, University of São Paulo; 2008. The selective serotonin reuptake inhibitors (SSRI) have been used successfully for the treatment of various psychiatry disorders. The SSRI clinical efficacy is attributed to an enhancement of the serotonergic neurotransmission, but little is known about the neuropsychological mechanisms underlying this process. Several evidences suggest that serotonin is involved with the regulation of social behavior, learning and memory process and emotional processing. The recognition of basic emotions on facial expressions represents an useful task to study the emotional processing, since they are a condensate, uniform and important stimuli for social functioning. The aim of the study was to verify the effects of the SSRI escitalopram on the recognition of facial emotional expressions. Twelve healthy males completed two experimental sessions each (crossover design), in a randomized, balanced order, double-blind design. An oral dose of 10 mg of escitalopram was administered 3 hours before they performed an emotion recognition task with six basic emotions angry, fear, sadness, disgust, happiness and surprise and neutral expression. The faces were digitally morphed between 10% and 100% of each emotional standard, creating a 10% steps gradient. The subjective mood and anxiety states through the task were recorded and the performance through the task was defined by the accuracy measure (number of correct answers divided by the total of stimuli presented). In general, except of fear, escitalopram interfered with all the emotions tested. Specifically, facilitated the recognition of sadness, while impaired the identification of happiness. When the gender of the faces was analyzed, this effect was seen in male, but not female faces, where it improves the recognition of happiness. In addition, improves the recognition of angry and disgusted faces when administered at the second session and impaired the identification of surprised faces at intermediate levels of intensity. It also showed a global positive effect on task performance when administered at the second session. The results indicate a serotonergic modulation on the recognition of emotional faces and the recall of previous learned items.

Antidepressivos clássicos apresentam uma série de limitações na prática clínica, sendo uma das mais relevantes a latência de 4 a 8 semanas para indução de uma melhora significativa dos sintomas. Existem evidências que canabinóides, como o fitocanabinóide canabidiol (CBD) e o inibidor de degradação da anandamida URB597 (URB) geram efeitos comportamentais semelhantes aos antidepressivos. Canabinóides e antidepressivos podem, inclusive, apresentar mecanismos moleculares em comum. O presente estudo investigou os efeitos comportamentais e neuroplásticos de uma semana de tratamento com a combinação de uma dose do antidepressivo escitalopram (ESC) que gera efeitos comportamentais após 3 semanas de tratamento com doses sub-efetivas de canabinóides em camundongos estressados. Para isso, camundongos C57Bl6 machos foram submetidos ao protocolo de estresse crônico imprevisível (CUS) ou ao protocolo de estresse de derrota social (SDS) por 10 dias. Os animais foram divididos em 7 grupos experimentais (n=8-13; Controle (Não estressado); Veículo (Veí/Veí); ESC 10mg/kg (Esc/Veí); CBD 7,5 mg/kg (Veí/CBD); URB 0,1 mg/kg (Veí/CBD); ESC/CBD; ESC/URB) e foram tratados durante os 7 últimos dias do protocolo de estresse (via i.p.). O tratamento com a combinação de escitalopram e CBD gerou respostas preditivas de um efeito do tipo-antidepressivo no teste de suspensão pela cauda e de um efeito do tipo-ansiolítico no novelty suppressed feeding tanto no modelo de estresse homotípico (SDS) quanto no modelo de estresse heterotípico (CUS). Paralelamente às alterações comportamentais, foi observado que o grupo ESC/CBD apresentou uma maior expressão relativa de sinaptofisina no córtex pré-frontal, evidenciando um possível efeito pró-sinaptogênico da combinação. Esse mesmo tratamento promoveu aumento na expressão de sinaptotagmina e ?-actina no hipocampo. Os resultados encontrados no presente estudo evidenciam que a combinação com CBD pode otimizar a ação do antidepressivo escitalopram. / Despite their widespread use, antidepressant drugs show some limitations in the clinical practice, including a delayed onset of action. Cannabinoid drugs, such as canabidiol (CBD) and the anandamide degradation inhibitor URB597 (URB), have shown behavioral effects that are similar to those induced by antidepressants in preclinical studies. Antidepressants and cannabinoids might even share common mechanisms. This study aimed to evaluate the behavioral and neuroplastic effects of one week of treatment of stressed animals with the combination of sub-effective doses of cannabinoids with 10mg/Kg of escitalopram (ESC)- dose that prevented- stressinduced behavioural changes only after 3 weeks of treatment. Male C57Bl6 mice were subjected to a 10-day protocol of either social defeat stress (SDS) or chronic unpredictable stress (CUS). Animals were divided in 7 experimental groups (n=8-13; Control (Non-stressed); Vehicle (Veh/Veh); ESC 10mg/kg (Esc/Veh); CBD 7,5mg/kg (Veh/CBD); URB 0,1mg/kg (Veh/CBD); ESC/CBD; ESC/URB) and the treatment was conducted during the 7 last days of the stress protocol (via i.p.). The treatment with the combination of ESC and CBD produced responses that are considered predictive of antidepressant-like effects in the tail suspension test and of anxiolytic-like effects in the novelty suppressed feeding in both the homotypic stress (SDS) and the heterotypic stress (CUS) models. In paralel with the bevavioral outcomes, molecular analysis revealed that the ESC/CBD group showed a higher relative expression of synaptophysin in the PFC, suggesting a pro-synaptogenic effect of the combination. Increased relative expression of synaptotagmin and ?-actin in the hippocampus following ESC/CBD treatment were also reported. The results presented in this study provide evidence that the combination with CBD can optimize the action of the antidepressant escitalopram.

ALVES NETO, W.C. Efeitos do escitalopram sobre a identificação de expressões faciais. Ribeirão Preto, SP: Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo; 2008. Os inibidores seletivos da recaptura de serotonina (ISRS) têm sido utilizados com sucesso para o tratamento de diversas patologias psiquiátricas. Sua eficácia clínica é atribuída a uma potencialização da neurotransmissão serotoninérgica, mas pouco ainda é conhecido sobre os mecanismos neuropsicológicos envolvidos nesse processo. Várias evidências sugerem que a serotonina estaria envolvida, entre outras funções, na regulação do comportamento social, nos processos de aprendizagem e memória e no processamento de emoções. O reconhecimento de expressões faciais de emoções básicas representa um valioso paradigma para o estudo do processamento de emoções, pois são estímulos condensados, uniformes e de grande relevância para o funcionamento social. O objetivo do estudo foi avaliar os efeitos da administração aguda e por via oral do escitalopram, um ISRS, no reconhecimento de expressões faciais de emoções básicas. Uma dose oral de 10 mg de escitalopram foi administrada a doze voluntários saudáveis do sexo masculino, em modelo duplo-cego, controlado por placebo, em delineamento cruzado, ordem randômica, 3 horas antes de realizarem a tarefa de reconhecimento de expressões faciais, com seis emoções básicas raiva, medo, tristeza, asco, alegria e surpresa mais a expressão neutra. As faces foram digitalmente modificadas de forma a criar um gradiente de intensidade entre 10 e 100% de cada emoção, com incrementos sucessivos de 10%. Foram registrados os estados subjetivos de humor e ansiedade ao longo da tarefa e o desempenho foi avaliado pela medida de acurácia (número de acertos sobre o total de estímulos apresentados). De forma geral, o escitalopram interferiu no reconhecimento de todas as expressões faciais, à exceção de medo. Especificamente, facilitou a identificação das faces de tristeza e prejudicou o reconhecimento de alegria. Quando considerado o gênero das faces, esse efeito foi observado para as faces masculinas, enquanto que para as faces femininas o escitalopram não interferiu com o reconhecimento de tristeza e aumentou o de alegria. Além disso, aumentou o reconhecimento das faces de raiva e asco quando administrado na segunda sessão e prejudicou a identificação das faces de surpresa nas intensidades intermediárias de gradação. Também apresentou um efeito positivo global sobre o desempenho na tarefa quando administrado na segunda sessão. Os resultados sugerem uma modulação serotoninérgica sobre o reconhecimento de expressões faciais emocionais e sobre a evocação de material previamente aprendido. / ALVES NETO, W.C. Effects of escitalopram on the processing of emotional faces. Ribeirão Preto, SP: Faculty of Medicine of Ribeirão Preto, University of São Paulo; 2008. The selective serotonin reuptake inhibitors (SSRI) have been used successfully for the treatment of various psychiatry disorders. The SSRI clinical efficacy is attributed to an enhancement of the serotonergic neurotransmission, but little is known about the neuropsychological mechanisms underlying this process. Several evidences suggest that serotonin is involved with the regulation of social behavior, learning and memory process and emotional processing. The recognition of basic emotions on facial expressions represents an useful task to study the emotional processing, since they are a condensate, uniform and important stimuli for social functioning. The aim of the study was to verify the effects of the SSRI escitalopram on the recognition of facial emotional expressions. Twelve healthy males completed two experimental sessions each (crossover design), in a randomized, balanced order, double-blind design. An oral dose of 10 mg of escitalopram was administered 3 hours before they performed an emotion recognition task with six basic emotions angry, fear, sadness, disgust, happiness and surprise and neutral expression. The faces were digitally morphed between 10% and 100% of each emotional standard, creating a 10% steps gradient. The subjective mood and anxiety states through the task were recorded and the performance through the task was defined by the accuracy measure (number of correct answers divided by the total of stimuli presented). In general, except of fear, escitalopram interfered with all the emotions tested. Specifically, facilitated the recognition of sadness, while impaired the identification of happiness. When the gender of the faces was analyzed, this effect was seen in male, but not female faces, where it improves the recognition of happiness. In addition, improves the recognition of angry and disgusted faces when administered at the second session and impaired the identification of surprised faces at intermediate levels of intensity. It also showed a global positive effect on task performance when administered at the second session. The results indicate a serotonergic modulation on the recognition of emotional faces and the recall of previous learned items.

Antidepressivos clássicos apresentam uma série de limitações na prática clínica, sendo uma das mais relevantes a latência de 4 a 8 semanas para indução de uma melhora significativa dos sintomas. Existem evidências que canabinóides, como o fitocanabinóide canabidiol (CBD) e o inibidor de degradação da anandamida URB597 (URB) geram efeitos comportamentais semelhantes aos antidepressivos. Canabinóides e antidepressivos podem, inclusive, apresentar mecanismos moleculares em comum. O presente estudo investigou os efeitos comportamentais e neuroplásticos de uma semana de tratamento com a combinação de uma dose do antidepressivo escitalopram (ESC) que gera efeitos comportamentais após 3 semanas de tratamento com doses sub-efetivas de canabinóides em camundongos estressados. Para isso, camundongos C57Bl6 machos foram submetidos ao protocolo de estresse crônico imprevisível (CUS) ou ao protocolo de estresse de derrota social (SDS) por 10 dias. Os animais foram divididos em 7 grupos experimentais (n=8-13; Controle (Não estressado); Veículo (Veí/Veí); ESC 10mg/kg (Esc/Veí); CBD 7,5 mg/kg (Veí/CBD); URB 0,1 mg/kg (Veí/CBD); ESC/CBD; ESC/URB) e foram tratados durante os 7 últimos dias do protocolo de estresse (via i.p.). O tratamento com a combinação de escitalopram e CBD gerou respostas preditivas de um efeito do tipo-antidepressivo no teste de suspensão pela cauda e de um efeito do tipo-ansiolítico no novelty suppressed feeding tanto no modelo de estresse homotípico (SDS) quanto no modelo de estresse heterotípico (CUS). Paralelamente às alterações comportamentais, foi observado que o grupo ESC/CBD apresentou uma maior expressão relativa de sinaptofisina no córtex pré-frontal, evidenciando um possível efeito pró-sinaptogênico da combinação. Esse mesmo tratamento promoveu aumento na expressão de sinaptotagmina e ?-actina no hipocampo. Os resultados encontrados no presente estudo evidenciam que a combinação com CBD pode otimizar a ação do antidepressivo escitalopram. / Despite their widespread use, antidepressant drugs show some limitations in the clinical practice, including a delayed onset of action. Cannabinoid drugs, such as canabidiol (CBD) and the anandamide degradation inhibitor URB597 (URB), have shown behavioral effects that are similar to those induced by antidepressants in preclinical studies. Antidepressants and cannabinoids might even share common mechanisms. This study aimed to evaluate the behavioral and neuroplastic effects of one week of treatment of stressed animals with the combination of sub-effective doses of cannabinoids with 10mg/Kg of escitalopram (ESC)- dose that prevented- stressinduced behavioural changes only after 3 weeks of treatment. Male C57Bl6 mice were subjected to a 10-day protocol of either social defeat stress (SDS) or chronic unpredictable stress (CUS). Animals were divided in 7 experimental groups (n=8-13; Control (Non-stressed); Vehicle (Veh/Veh); ESC 10mg/kg (Esc/Veh); CBD 7,5mg/kg (Veh/CBD); URB 0,1mg/kg (Veh/CBD); ESC/CBD; ESC/URB) and the treatment was conducted during the 7 last days of the stress protocol (via i.p.). The treatment with the combination of ESC and CBD produced responses that are considered predictive of antidepressant-like effects in the tail suspension test and of anxiolytic-like effects in the novelty suppressed feeding in both the homotypic stress (SDS) and the heterotypic stress (CUS) models. In paralel with the bevavioral outcomes, molecular analysis revealed that the ESC/CBD group showed a higher relative expression of synaptophysin in the PFC, suggesting a pro-synaptogenic effect of the combination. Increased relative expression of synaptotagmin and ?-actin in the hippocampus following ESC/CBD treatment were also reported. The results presented in this study provide evidence that the combination with CBD can optimize the action of the antidepressant escitalopram.

In der Pathophysiologie der Depression könnte das Zusammenspiel von Immun- und Nervensystem eine zentrale Rolle spielen. In den Krankheitsepisoden zeigen depressive Patienten eine gesteigerte Produktion pro-inflammatorischer Zytokine wie z. B. Interleukin (IL)-1β und dem Tumornekrosefaktor (TNF)-α. Es gibt nur begrenzte Informationen bezüglich der Effekte von Antidepressiva auf Zytokine. Die meisten Studien berichten nur über die Veränderungen einzelner Zytokine und keine hat bis jetzt über Effekte von Antidepressiva auf IL-22 berichtet. Wir haben systematisch die Wirkung von drei Antidepressiva, nämlich Citalopram, Escitalopram und Mirtazapin auf die Sekretion der Zytokine IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 und TNF-α in einem Vollblutverfahren in-vitro untersucht. Als Immunstimulanzien wurden der gegen humanes CD3 gerichtete monoklonale Antikörper OKT3 und der gegen CD40 gerichtete monoklonale Antikörper 5C3 verwendet. Es zeigte sich, dass es unter Citalopram zu einer erhöhten IL-1β, I-6, IL-22 und TNF-α-Produktion und unter Mirtazapin zu einer erhöhten Produktion von IL-1β, IL-22 und TNF-α gegenüber der Kontrollbedingung, in der keine Antidepressiva zugesetzt wurden, kam. Unter Escitalopram kam es zu einer gegenüber der Kontrollbedingung verringerten IL-17-Produktion. Der Einfluss der Antidepressiva auf IL-2 und IL-4 war für alle drei Psychopharmaka nicht signifikant. Verglichen mit Escitalopram führte Citalopram zu höheren IL-1β-, IL-6-, IL-17- und IL-22-Konzentrationen und Mirtazapin führte zu einer höheren IL-1β-, IL-17-, IL-22- und TNF-α-Produktion. Möglicherweise besteht ein Bezug zwischen dem Profil der Zytokinproduktion eines Antidepressivums und seinen therapeutischen Effekten, Nebenwirkungen und seinem Rückfallrisiko. Zur Überprüfung dieser Hypothese sind jedoch in-vivo Studien notwendig. / The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively.Citalopram increased production of IL-1β, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1β, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1β, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1β, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects.

ithium is an important psychopharmacologi- cal agent for the treatment of unipolar as well as bipolar affective disorders. Lithium has a number of side effects such as hypothyroidism and aggravation of psoriasis. On the other hand, lithium has pro-inflammatory effects, which appear beneficial in some disorders associated with immunological deficits, such as human immunodeficiency virus (HIV) infection and systemic lupus erythematosus (SLE). Therefore, immunological characteristics of lithium may be an important consideration in individualized ther- apeutic decisions. We measured the levels of the cytokines interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-22, IL-17 and tumour necrosis factor (TNF)-a in the stimulated blood of thirty healthy subjects supplemented with lithium alone, the antidepressants citalopram, escitalopram or mirtazapine alone, the combination of each antidepressant with lithium, and a no drug control. These drugs were tested under three blood stimulant conditions: murine anti-human CD3 monoclonal antibody OKT3 and the 5C3 monoclonal antibody (OKT3/5C3), phytohemagglutinin (PHA), and unstimulated blood. Lithium, alone and in combination with any of the tested antidepressants, led to a consistent increase of IL-1ß, IL-6 and TNF-a levels in the unstimulated as well as the stimulated blood. In the OKT3/ 5C3- and PHA-stimulated blood, IL-17 production was significantly enhanced by lithium. Lithium additionally increased IL-2 concentrations significantly in PHA-stimu- lated blood. The data support the view that lithium has pro- inflammatory properties. These immunological character- istics may contribute to side effects of lithium, but may also explain its beneficial effects in patients suffering from HIV infection or SLE.