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.

Syftet med den här studien är att utreda om det finns något samband mellan den psykiska ohälsan och konjunkturcykeln i Sverige. Relationen är viktig att undersöka på grund av att en försämring av psykisk hälsa som ett resultat av ekonomiska kriser, skulle kunna leda till ytterligare kostnader såsom förlorad produktion. För att kunna sätta in relevanta insatser och eventuellt lindra negativa effekter, studeras det också om det finns skillnader mellan män och kvinnor. Indikatorer för psykisk ohälsa som används för att besvara syftet är förekomsten av suicid, användning av antidepressiva, depression samt psykiatriska tillstånd. Som konjunkturmått används bruttoregionprodukt och arbetslöshet. Ytterligare kontrollvariabler som andel utrikesfödda, befolkningstäthet och andel av befolkningen med högre utbildning inkluderas också. Regressionsanalyser görs på två olika modeller, där modell 1 fångar upp sambandet mellan ohälsa och konjunkturförändringar och modell 2 fångar upp skillnaden mellan könen. Resultatet är att under lågkonjunktur minskar användningen av antidepressiva, men ingen förändring för depression eller psykiatriska tillstånd observeras. Resultatet angående suicid är att under lågkonjunktur minskar suicidgraden mer för kvinnor än för män. Detta innebär att det delvis finns ett samband mellan konjunkturförändringar och psykisk ohälsa i Sverige. / The purpose of this study is to investigate if mental health in Sweden is connected to the business cycle. The relationship is important to investigate since deterioration of mental health, due to economic crises, could lead to additional costs in the form of losses in production. To be able to make relevant decisions to mitigate any negative effects, the question of whether there is a difference between men and women is also studied. The four different indicators that are used to describe mental illness are: suicide, antidepressants, depression, and psychiatric conditions. Gross regional product and unemployment are used as economic indicators. Additional control variables such as the share of foreign-born individuals, population density, and the share of individuals with tertiary degrees are also included. Furthermore, the regression analyses are made based on two types of models. Model number one captures the relation between mental illness and changes in business cycle, while model number two captures the difference in mental illness between genders. The results show that during recessions the consumption of antidepressants decreases while there is no change in depression and psychiatric conditions. Whereas results regarding suicide show that during recessions suicide for women decrease more than for men. This means that there is a partial relationship between cyclical changes and mental illness in Sweden.

Bakgrund: Unga som varken arbetar eller studerar (UVAS) inkluderar 145 000 individer och utgör en stor utmaning för det svenska samhället. Syftet med denna studie var att närmare kartlägga gruppens karakteristika, att undersöka samvariationen mellan kommuner med hög andel UVAS och deras geografiska beskaffenhet samt förskrivning av psykofarmaka. Metod: Studien utformades som en retrospektiv tvärsnittsstudie baserad på registerdata hämtad från Myndigheten för ungdoms- och civilsamhällesfrågor (MUCF). Resultat: Datan påvisade en jämn könsfördelning i UVAS-gruppen men en högre andel äldre (25–29) och utlandsfödda individer sågs jämfört med åldersgruppen som helhet. Bivariata analyser med Chi2-test påvisade statistiskt signifikanta samvariationer mellan hög andel UVAS i kommunen och kön, högre ålder (25–29) samt utländsk härkomst. Inga statistiskt signifikanta samvariationer återfanns mellan andel UVAS och kommunens storlek men däremot med geografisk lokalisation (nordlig/sydlig). Inget samband påvisades med förskrivningen av psykofarmaka. Slutsats: Att UVAS-gruppen i högre grad inkluderar äldre individer och utlandsfödda stämmer väl överens med internationell forskning. Frånvaron av samvariation mellan andelen UVAS i kommunen och dess geografiska beskaffenhet var något förvånande och skiljer sig från tidigare forskning men skulle kunna förklaras av ett gott samhällsstöd i Sverige. Vikten av ett signifikant bortfall i studien kan ej förringas. Att förskrivningen av psykofarmaka saknar samvariation med hög andel UVAS kan delvis förklaras av brister i statistiken men det kan ej uteslutas att ett sådant samband saknas. Framöver behövs ytterligare studier för att undersöka hur de med sämst förutsättning för att lämna UVAS-gruppen kan bli hjälpta. / <p>Betyg i Ladok 220601.</p>

The objective was to examine duloxetine 60–120mg/day treatment for relapse prevention in adults with generalized anxiety disorder (GAD). Adult patients (N=887; mean age=43.3 years; 61.0% female) with DSM-IV-TR-defined GAD diagnosis were treated with duloxetine for 26 weeks. Patients who completed open-label phase and were treatment responders (≥50% reduction in Hamilton Anxiety Rating Scale total score to ≤11 and “much”/“very much improved” ratings for the last 2 visits of open-label phase) were randomly assigned to receive duloxetine or placebo for a 26-week double-blind continuation phase. Relapse was defined as ≥2-point increase in illness severity ratings or by discontinuation due to lack of efficacy. During the double-blind phase, placebo-treated patients (N=201) relapsed more frequently (41.8%) than duloxetine-treated patients (13.7%, N=204, P≤0.001) and worsened on each outcome measure (P≤0.001, all comparisons). Duloxetine 60–120 mg/day treatment was efficacious and reduced risk of relapse in patients with GAD.

No description available.

Background: The late onset of therapeutic response and a relatively large proportion of nonresponders to antidepressants remain major concerns in clinical practice. Therefore, there is a critical need for effective medication strategies that augment treatment with antidepressants. Methods: To review the available evidence on the use of lithium as an augmentation strategy to treat depressive episodes. Results: More than 30 open-label studies and 10 placebo-controlled double-blind trials have demonstrated substantial efficacy of lithium augmentation in the acute treatment of depressive episodes. Most of these studies were performed in unipolar depression and included all major classes of antidepressants, however mostly tricyclics. A meta-analysis including 10 randomized placebo-controlled trials has provided evidence that lithium augmentation has a statistically significant effect on the response rate compared to placebo with an odds ratio of 3.11, which corresponds to a number-needed-to-treat of 5. The meta-analysis revealed a mean response rate of 41.2% in the lithium group and 14.4% in the placebo group. One placebo-controlled trial in the continuation treatment phase showed that responders to acute-phase lithium augmentation should be maintained on the lithium-antidepressant combination for at least 12 months to prevent early relapses. Preliminary studies to assess genetic influences on response probability to lithium augmentation have suggested a predictive role of the –50T/C single nucleotide polymorphism of the GSK3β gene. Conclusion: Augmentation of antidepressants with lithium is currently the best-evidenced augmentation therapy in the treatment of depressed patients who do not respond to antidepressants. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 5 uppsatser.

O objetivo deste trabalho foi ampliar o estudo do mecanismo de ação antidepressivo de Hypericum polyanthemum (POL) e de seu composto derivado da classe dos floroglucinóis uliginosina B (ULI). Considerando o potencial desta planta para o desenvolvimento de novos fármacos, realizou-se um estudo pré-clínico de toxicidade aguda e doses repetidas de POL em camundongos. A administração via oral (v.o.) do extrato ciclo-hexano de POL (90 mg/kg) foi capaz de reduzir significativamente o tempo de imobilidade de ratos e camundongos no teste de natação forçada (TNF). A administração de ULI (10 mg/kg, v.o.) igualmente reduziu o tempo de imobilidade no TNF e também no teste de suspensão pela cauda (TSC). A administração simultânea (v.o), das subdoses de POL (45 mg/kg) e ULI (5 mg/kg) foram capazes de potencializar o efeito antidepressivo das subdoses de imipramina (10 mg/kg), bupropiona (3 mg/kg) e fluoxetina (15 mg/kg), no TNF em camundongos. O pré- tratamento de camundongos, pela via intraperitoneal, com SCH 23390 (antagonista de receptor dopaminérgico D1); sulpirida (antagonista de receptor dopaminérgico D2); prazosin (antagonista de receptor α1-adrenérgico); ioimbina (antagonista de receptor α2-adrenérgico) e p-clorofenilalanina metil éster (pCPA- inibidor da síntese de serotonina (5-HT), preveniu o efeito anti-imobilidade de ULI no TNF. In vitro, ULI inibiu a recaptação sinaptossomal de dopamina ([3H]-DA), noradrenalina ([3H]-NA) e serotonina ([3H]-5-HT), sem ligação aos transportadores, e isto foi demonstrado através das diferentes concentrações de ULI que não afetaram a ligação de [3H]- mazindol, [3H]-nisoxetina e [3H]-citalopram aos sítios de recaptação de DA, NA e 5- HT, respectivamente. Estes resultados sugerem que ULI tem ação não-seletiva sobre o sistema monoaminérgico, o que pode representar um novo composto com inibição tripla da recaptação; além disso possui mecanismo de ação diferente dos antidepressivos clássicos, inibindo a recaptação das monoaminas sem se ligar aos respectivos sítios específicos dos transportadores. Também realizou-se estudo bioquímico da atividade da Na+,K+-ATPase em córtex cerebral e hipocampo de camundongos. O tratamento agudo e repetido por via oral (3 dias, 1 x ao dia) aumentou a atividade desta enzima em córtex cerebral de camundongos em diferentes tempos. ULI não alterou a atividade da Na+,K+-ATPase em hipocampo dos camundongos, e esse resultado corrobora com a hipótese de que ULI pode estar contribuindo para a manutenção da excitabilidade neuronal estimulando esta enzima, e agindo seletivamente no córtex cerebral. Além disso, investigou-se o papel de ULI sobre os canais de sódio dependentes de voltagem (Na+), através da pré-administração de veratrina (ativador de canal de Na+). A veratrina bloqueou o efeito antidepressivo de ULI no TNF e este resultado indica a possibilidade de ULI estar bloqueando os canais de Na+ alterando o gradiente iônico através da estimulação da atividade da Na+,K+-ATPase e, prejudicando ou inibindo a recaptação das monoaminas. Nos experimentos de toxicidade, as mudanças fisiológicas, bioquímicas e histopatológicas mais pronunciadas foram observadas nos camundongos que receberam POL nas doses 5 e/ou 10 vezes maiores que a dose efetiva no TNF em camundongos. Entretanto, POL apresenta constituição química diferente de H. perforatum, sugerindo baixo risco desta espécie em relação à fototoxicidade (ausência de hipericina). Através dos dados obtidos neste estudo, acredita-se que POL pode se tornar uma espécie promissora no desenvolvimento de um novo fitoterápico com ação neuroativa. A inibição da recaptação das monoaminas pode estar relacionada a uma alteração do gradiente iônico de Na+, através da estimulação da atividade da Na+,K+-ATPase, o que leva a crer que ULI possui um perfil de ação lamotrigina-like. Dessa forma, ULI torna-se um novo e promissor padrão molecular de substância com atividade no sistema nervoso central. / The aim of this work was to continue studying the antidepressant mechanism of Hypericum polyanthemum (POL) and its compound derived from phloroglucinols class uliginosin B (ULI). Considering the potential for development of new drugs with this plant, a preclinical study of toxicity with POL was accomplished, administering acute and repeated-doses in mice. The cyclo-hexane extract administration by oral route (p.o.) of POL (90 mg/kg) was able to significantly reduce the immobility time of rats and mice in the forced swimming test (FST). ULI (10 mg/kg, p.o.) also produced a reduction in immobility time in two models predictive of antidepressant activity in mice, FST and the tail suspension test (TST). Simultaneously administration (p.o) of subeffective doses of POL (45 mg/kg) and ULI (5 mg/kg) were able to potentiate the antidepressant effect of subeffective dose of imipramine (10 mg/kg), bupropion (3 mg/kg ) and fluoxetine (15 mg/kg), in the mouse FST. The pretreatment of mice, by i.p. route, with SCH 23390 (dopamine D1 receptor antagonist); sulpiride (dopamine D2 receptor antagonist); (α1 adrenoceptor antagonist); yohimbine (α2 adrenoceptor antagonist) and p-chlorophenylalanine methyl ester (pCPA- an inhibitor of serotonin (5-HT) synthesis) prevented anti- immobility effect of ULI in FST. In vitro, ULI inhibited synaptosomal uptake of dopamine ([3H]-DA), noradrenaline ([3H]-NA) and 5-HT ([3H]-5-HT), without binding with monoaminergic transporters, and this was demonstrated by different concentrations of ULI that did not affect the binding of [3H]-mazindol, [3H]-nisoxetine and [3H]-citalopram to DA, NA and 5-HT uptake sites, respectively. These results suggest that ULI has non-selective action on the monoaminergic system, which may represent a new compound with triple reuptake inhibition; furthermore, ULI has a mechanism of action different from the classical antidepressants by inhibiting monoamine reuptake without bind to respective neurotransporters. In addition we have performed a biochemical study for activity of Na+, K+-ATPase in cerebral cortex and hippocampus of mice. Acute and repeated oral treatment (3 days, 1 x per day) increased enzyme activity in cortex at different times. ULI did not alter Na+, K+- ATPase activity in hippocampus, and this result confirms the hypothesis that ULI can be contributing to the maintenance of neuronal excitability by stimulating this enzyme, and acting selectively in cerebral cortex. Moreover, we investigated the role of ULI on voltage-gated sodium channels (Na+), through pre-administration of veratrine ( Na+ channel oppener). Veratrine was able to abolish the antidepressant effect of ULI in TNF and this result indicates the possibility that ULI blocks the Na+ channels by altering the ionic gradient through the stimulation of Na+, K+-ATPase and impairing or inhibiting the reuptake of monoamines. In toxicity experiments, the more pronounced physiological, biochemical and histopathological changes were observed in mice that received POL at doses 5 and/or 10 fold higher than the effective dose in TNF. However, POL has chemically different from H. perforatum, suggesting low risk of this species in relation to phototoxicity (absence of hypericin). Considering all results, we supposed that POL could be a product with potential for the development of new drugs. The monoamine reuptake inhibition can be related to a change on the gradient of Na+ ion, by stimulation of Na+, K+-ATPase, which suggests that ULI has a lamotrigine-like profile. Therefore, we suggest that phloroglucinol derivative ULI represents a promising new molecular pattern with central nervous system activity.

O objetivo deste trabalho foi ampliar o estudo do mecanismo de ação antidepressivo de Hypericum polyanthemum (POL) e de seu composto derivado da classe dos floroglucinóis uliginosina B (ULI). Considerando o potencial desta planta para o desenvolvimento de novos fármacos, realizou-se um estudo pré-clínico de toxicidade aguda e doses repetidas de POL em camundongos. A administração via oral (v.o.) do extrato ciclo-hexano de POL (90 mg/kg) foi capaz de reduzir significativamente o tempo de imobilidade de ratos e camundongos no teste de natação forçada (TNF). A administração de ULI (10 mg/kg, v.o.) igualmente reduziu o tempo de imobilidade no TNF e também no teste de suspensão pela cauda (TSC). A administração simultânea (v.o), das subdoses de POL (45 mg/kg) e ULI (5 mg/kg) foram capazes de potencializar o efeito antidepressivo das subdoses de imipramina (10 mg/kg), bupropiona (3 mg/kg) e fluoxetina (15 mg/kg), no TNF em camundongos. O pré- tratamento de camundongos, pela via intraperitoneal, com SCH 23390 (antagonista de receptor dopaminérgico D1); sulpirida (antagonista de receptor dopaminérgico D2); prazosin (antagonista de receptor α1-adrenérgico); ioimbina (antagonista de receptor α2-adrenérgico) e p-clorofenilalanina metil éster (pCPA- inibidor da síntese de serotonina (5-HT), preveniu o efeito anti-imobilidade de ULI no TNF. In vitro, ULI inibiu a recaptação sinaptossomal de dopamina ([3H]-DA), noradrenalina ([3H]-NA) e serotonina ([3H]-5-HT), sem ligação aos transportadores, e isto foi demonstrado através das diferentes concentrações de ULI que não afetaram a ligação de [3H]- mazindol, [3H]-nisoxetina e [3H]-citalopram aos sítios de recaptação de DA, NA e 5- HT, respectivamente. Estes resultados sugerem que ULI tem ação não-seletiva sobre o sistema monoaminérgico, o que pode representar um novo composto com inibição tripla da recaptação; além disso possui mecanismo de ação diferente dos antidepressivos clássicos, inibindo a recaptação das monoaminas sem se ligar aos respectivos sítios específicos dos transportadores. Também realizou-se estudo bioquímico da atividade da Na+,K+-ATPase em córtex cerebral e hipocampo de camundongos. O tratamento agudo e repetido por via oral (3 dias, 1 x ao dia) aumentou a atividade desta enzima em córtex cerebral de camundongos em diferentes tempos. ULI não alterou a atividade da Na+,K+-ATPase em hipocampo dos camundongos, e esse resultado corrobora com a hipótese de que ULI pode estar contribuindo para a manutenção da excitabilidade neuronal estimulando esta enzima, e agindo seletivamente no córtex cerebral. Além disso, investigou-se o papel de ULI sobre os canais de sódio dependentes de voltagem (Na+), através da pré-administração de veratrina (ativador de canal de Na+). A veratrina bloqueou o efeito antidepressivo de ULI no TNF e este resultado indica a possibilidade de ULI estar bloqueando os canais de Na+ alterando o gradiente iônico através da estimulação da atividade da Na+,K+-ATPase e, prejudicando ou inibindo a recaptação das monoaminas. Nos experimentos de toxicidade, as mudanças fisiológicas, bioquímicas e histopatológicas mais pronunciadas foram observadas nos camundongos que receberam POL nas doses 5 e/ou 10 vezes maiores que a dose efetiva no TNF em camundongos. Entretanto, POL apresenta constituição química diferente de H. perforatum, sugerindo baixo risco desta espécie em relação à fototoxicidade (ausência de hipericina). Através dos dados obtidos neste estudo, acredita-se que POL pode se tornar uma espécie promissora no desenvolvimento de um novo fitoterápico com ação neuroativa. A inibição da recaptação das monoaminas pode estar relacionada a uma alteração do gradiente iônico de Na+, através da estimulação da atividade da Na+,K+-ATPase, o que leva a crer que ULI possui um perfil de ação lamotrigina-like. Dessa forma, ULI torna-se um novo e promissor padrão molecular de substância com atividade no sistema nervoso central. / The aim of this work was to continue studying the antidepressant mechanism of Hypericum polyanthemum (POL) and its compound derived from phloroglucinols class uliginosin B (ULI). Considering the potential for development of new drugs with this plant, a preclinical study of toxicity with POL was accomplished, administering acute and repeated-doses in mice. The cyclo-hexane extract administration by oral route (p.o.) of POL (90 mg/kg) was able to significantly reduce the immobility time of rats and mice in the forced swimming test (FST). ULI (10 mg/kg, p.o.) also produced a reduction in immobility time in two models predictive of antidepressant activity in mice, FST and the tail suspension test (TST). Simultaneously administration (p.o) of subeffective doses of POL (45 mg/kg) and ULI (5 mg/kg) were able to potentiate the antidepressant effect of subeffective dose of imipramine (10 mg/kg), bupropion (3 mg/kg ) and fluoxetine (15 mg/kg), in the mouse FST. The pretreatment of mice, by i.p. route, with SCH 23390 (dopamine D1 receptor antagonist); sulpiride (dopamine D2 receptor antagonist); (α1 adrenoceptor antagonist); yohimbine (α2 adrenoceptor antagonist) and p-chlorophenylalanine methyl ester (pCPA- an inhibitor of serotonin (5-HT) synthesis) prevented anti- immobility effect of ULI in FST. In vitro, ULI inhibited synaptosomal uptake of dopamine ([3H]-DA), noradrenaline ([3H]-NA) and 5-HT ([3H]-5-HT), without binding with monoaminergic transporters, and this was demonstrated by different concentrations of ULI that did not affect the binding of [3H]-mazindol, [3H]-nisoxetine and [3H]-citalopram to DA, NA and 5-HT uptake sites, respectively. These results suggest that ULI has non-selective action on the monoaminergic system, which may represent a new compound with triple reuptake inhibition; furthermore, ULI has a mechanism of action different from the classical antidepressants by inhibiting monoamine reuptake without bind to respective neurotransporters. In addition we have performed a biochemical study for activity of Na+, K+-ATPase in cerebral cortex and hippocampus of mice. Acute and repeated oral treatment (3 days, 1 x per day) increased enzyme activity in cortex at different times. ULI did not alter Na+, K+- ATPase activity in hippocampus, and this result confirms the hypothesis that ULI can be contributing to the maintenance of neuronal excitability by stimulating this enzyme, and acting selectively in cerebral cortex. Moreover, we investigated the role of ULI on voltage-gated sodium channels (Na+), through pre-administration of veratrine ( Na+ channel oppener). Veratrine was able to abolish the antidepressant effect of ULI in TNF and this result indicates the possibility that ULI blocks the Na+ channels by altering the ionic gradient through the stimulation of Na+, K+-ATPase and impairing or inhibiting the reuptake of monoamines. In toxicity experiments, the more pronounced physiological, biochemical and histopathological changes were observed in mice that received POL at doses 5 and/or 10 fold higher than the effective dose in TNF. However, POL has chemically different from H. perforatum, suggesting low risk of this species in relation to phototoxicity (absence of hypericin). Considering all results, we supposed that POL could be a product with potential for the development of new drugs. The monoamine reuptake inhibition can be related to a change on the gradient of Na+ ion, by stimulation of Na+, K+-ATPase, which suggests that ULI has a lamotrigine-like profile. Therefore, we suggest that phloroglucinol derivative ULI represents a promising new molecular pattern with central nervous system activity.

O objetivo deste trabalho foi ampliar o estudo do mecanismo de ação antidepressivo de Hypericum polyanthemum (POL) e de seu composto derivado da classe dos floroglucinóis uliginosina B (ULI). Considerando o potencial desta planta para o desenvolvimento de novos fármacos, realizou-se um estudo pré-clínico de toxicidade aguda e doses repetidas de POL em camundongos. A administração via oral (v.o.) do extrato ciclo-hexano de POL (90 mg/kg) foi capaz de reduzir significativamente o tempo de imobilidade de ratos e camundongos no teste de natação forçada (TNF). A administração de ULI (10 mg/kg, v.o.) igualmente reduziu o tempo de imobilidade no TNF e também no teste de suspensão pela cauda (TSC). A administração simultânea (v.o), das subdoses de POL (45 mg/kg) e ULI (5 mg/kg) foram capazes de potencializar o efeito antidepressivo das subdoses de imipramina (10 mg/kg), bupropiona (3 mg/kg) e fluoxetina (15 mg/kg), no TNF em camundongos. O pré- tratamento de camundongos, pela via intraperitoneal, com SCH 23390 (antagonista de receptor dopaminérgico D1); sulpirida (antagonista de receptor dopaminérgico D2); prazosin (antagonista de receptor α1-adrenérgico); ioimbina (antagonista de receptor α2-adrenérgico) e p-clorofenilalanina metil éster (pCPA- inibidor da síntese de serotonina (5-HT), preveniu o efeito anti-imobilidade de ULI no TNF. In vitro, ULI inibiu a recaptação sinaptossomal de dopamina ([3H]-DA), noradrenalina ([3H]-NA) e serotonina ([3H]-5-HT), sem ligação aos transportadores, e isto foi demonstrado através das diferentes concentrações de ULI que não afetaram a ligação de [3H]- mazindol, [3H]-nisoxetina e [3H]-citalopram aos sítios de recaptação de DA, NA e 5- HT, respectivamente. Estes resultados sugerem que ULI tem ação não-seletiva sobre o sistema monoaminérgico, o que pode representar um novo composto com inibição tripla da recaptação; além disso possui mecanismo de ação diferente dos antidepressivos clássicos, inibindo a recaptação das monoaminas sem se ligar aos respectivos sítios específicos dos transportadores. Também realizou-se estudo bioquímico da atividade da Na+,K+-ATPase em córtex cerebral e hipocampo de camundongos. O tratamento agudo e repetido por via oral (3 dias, 1 x ao dia) aumentou a atividade desta enzima em córtex cerebral de camundongos em diferentes tempos. ULI não alterou a atividade da Na+,K+-ATPase em hipocampo dos camundongos, e esse resultado corrobora com a hipótese de que ULI pode estar contribuindo para a manutenção da excitabilidade neuronal estimulando esta enzima, e agindo seletivamente no córtex cerebral. Além disso, investigou-se o papel de ULI sobre os canais de sódio dependentes de voltagem (Na+), através da pré-administração de veratrina (ativador de canal de Na+). A veratrina bloqueou o efeito antidepressivo de ULI no TNF e este resultado indica a possibilidade de ULI estar bloqueando os canais de Na+ alterando o gradiente iônico através da estimulação da atividade da Na+,K+-ATPase e, prejudicando ou inibindo a recaptação das monoaminas. Nos experimentos de toxicidade, as mudanças fisiológicas, bioquímicas e histopatológicas mais pronunciadas foram observadas nos camundongos que receberam POL nas doses 5 e/ou 10 vezes maiores que a dose efetiva no TNF em camundongos. Entretanto, POL apresenta constituição química diferente de H. perforatum, sugerindo baixo risco desta espécie em relação à fototoxicidade (ausência de hipericina). Através dos dados obtidos neste estudo, acredita-se que POL pode se tornar uma espécie promissora no desenvolvimento de um novo fitoterápico com ação neuroativa. A inibição da recaptação das monoaminas pode estar relacionada a uma alteração do gradiente iônico de Na+, através da estimulação da atividade da Na+,K+-ATPase, o que leva a crer que ULI possui um perfil de ação lamotrigina-like. Dessa forma, ULI torna-se um novo e promissor padrão molecular de substância com atividade no sistema nervoso central. / The aim of this work was to continue studying the antidepressant mechanism of Hypericum polyanthemum (POL) and its compound derived from phloroglucinols class uliginosin B (ULI). Considering the potential for development of new drugs with this plant, a preclinical study of toxicity with POL was accomplished, administering acute and repeated-doses in mice. The cyclo-hexane extract administration by oral route (p.o.) of POL (90 mg/kg) was able to significantly reduce the immobility time of rats and mice in the forced swimming test (FST). ULI (10 mg/kg, p.o.) also produced a reduction in immobility time in two models predictive of antidepressant activity in mice, FST and the tail suspension test (TST). Simultaneously administration (p.o) of subeffective doses of POL (45 mg/kg) and ULI (5 mg/kg) were able to potentiate the antidepressant effect of subeffective dose of imipramine (10 mg/kg), bupropion (3 mg/kg ) and fluoxetine (15 mg/kg), in the mouse FST. The pretreatment of mice, by i.p. route, with SCH 23390 (dopamine D1 receptor antagonist); sulpiride (dopamine D2 receptor antagonist); (α1 adrenoceptor antagonist); yohimbine (α2 adrenoceptor antagonist) and p-chlorophenylalanine methyl ester (pCPA- an inhibitor of serotonin (5-HT) synthesis) prevented anti- immobility effect of ULI in FST. In vitro, ULI inhibited synaptosomal uptake of dopamine ([3H]-DA), noradrenaline ([3H]-NA) and 5-HT ([3H]-5-HT), without binding with monoaminergic transporters, and this was demonstrated by different concentrations of ULI that did not affect the binding of [3H]-mazindol, [3H]-nisoxetine and [3H]-citalopram to DA, NA and 5-HT uptake sites, respectively. These results suggest that ULI has non-selective action on the monoaminergic system, which may represent a new compound with triple reuptake inhibition; furthermore, ULI has a mechanism of action different from the classical antidepressants by inhibiting monoamine reuptake without bind to respective neurotransporters. In addition we have performed a biochemical study for activity of Na+, K+-ATPase in cerebral cortex and hippocampus of mice. Acute and repeated oral treatment (3 days, 1 x per day) increased enzyme activity in cortex at different times. ULI did not alter Na+, K+- ATPase activity in hippocampus, and this result confirms the hypothesis that ULI can be contributing to the maintenance of neuronal excitability by stimulating this enzyme, and acting selectively in cerebral cortex. Moreover, we investigated the role of ULI on voltage-gated sodium channels (Na+), through pre-administration of veratrine ( Na+ channel oppener). Veratrine was able to abolish the antidepressant effect of ULI in TNF and this result indicates the possibility that ULI blocks the Na+ channels by altering the ionic gradient through the stimulation of Na+, K+-ATPase and impairing or inhibiting the reuptake of monoamines. In toxicity experiments, the more pronounced physiological, biochemical and histopathological changes were observed in mice that received POL at doses 5 and/or 10 fold higher than the effective dose in TNF. However, POL has chemically different from H. perforatum, suggesting low risk of this species in relation to phototoxicity (absence of hypericin). Considering all results, we supposed that POL could be a product with potential for the development of new drugs. The monoamine reuptake inhibition can be related to a change on the gradient of Na+ ion, by stimulation of Na+, K+-ATPase, which suggests that ULI has a lamotrigine-like profile. Therefore, we suggest that phloroglucinol derivative ULI represents a promising new molecular pattern with central nervous system activity.