RESUMO
BACKGROUND: Many depressed patients are not able to achieve or sustain symptom remission despite serial treatment trials - often termed "treatment resistant depression". A broader, perhaps more empathic concept of "difficult-to-treat depression" (DTD) was considered. METHODS: A consensus group discussed the definition, clinical recognition, assessment and management implications of the DTD heuristic. RESULTS: The group proposed that DTD be defined as "depression that continues to cause significant burden despite usual treatment efforts". All depression management should include a thorough initial assessment. When DTD is recognized, a regular reassessment that employs a multi-dimensional framework to identify addressable barriers to successful treatment (including patient-, illness- and treatment-related factors) is advised, along with specific recommendations for addressing these factors. The emphasis of treatment, in the first instance, shifts from a goal of remission to optimal symptom control, daily psychosocial functional and quality of life, based on a patient-centred approach with shared decision-making to enhance the timely consideration of all treatment options (including pharmacotherapy, psychotherapy, neurostimulation, etc.) to optimize outcomes when sustained remission is elusive. LIMITATIONS: The recommended definition and management of DTD is based largely on expert consensus. While DTD would seem to have clinical utility, its specificity and objectivity may be insufficient to define clinical populations for regulatory trial purposes, though DTD could define populations for service provision or phase 4 trials. CONCLUSIONS: DTD provides a clinically useful conceptualization that implies a search for and remediation of specific patient-, illness- and treatment obstacles to optimizing outcomes of relevance to patients.
Assuntos
Depressão , Transtorno Depressivo Resistente a Tratamento , Consenso , Humanos , Psicoterapia , Qualidade de VidaRESUMO
Wf-516 is a potential novel antidepressant. It has high affinity for serotonin (5-hydroxytryptamine; 5-HT) transporters, 5-HT(1A) and 5-HT(2A) receptors. In the present study, the pharmacologic properties of Wf-516 were thus assessed using in vivo electrophysiology in the rat dorsal raphe nucleus (DRN), locus coeruleus (LC) and hippocampus. Glass microelectrodes were lowered into the DRN, LC or hippocampus, and neurons were recorded and tested using systemic or microiontophoretic injections of drugs. In the DRN, cumulative doses of 0.5 mg/kg of Wf-516 were injected intravenously and total inhibition of 5-HT neurons firing was obtained with 2.8 +/- 0.3 mg/kg. The administration of 1 mg/kg of Wf-516, which by itself did not induce a change in the firing of 5-HT neurons, markedly attenuated the inhibitory effect of the 5-HT(1A) autoreceptor agonist LSD, indicating that Wf-516 is a 5-HT(1A) autoreceptor antagonist. In the LC, 1 mg/kg of Wf-516 dampened the inhibitory effect of the preferential 5-HT(2A) agonist DOI on norepinephrine (NE) neurons, indicating that Wf-516 is also a 5-HT(2A) receptor antagonist. In the hippocampus, cumulative intravenous doses of Wf-516 significantly increased the recovery time of firing activity of CA(3) pyramidal neurons after 5-HT applications, indicating an inhibitory effect on 5-HT reuptake. Unlike the 5-HT(1A) antagonist WAY100635, Wf-516 did not block the inhibitory effect of microiontophoretic application of 5-HT, indicating that this drug is devoid of 5-HT(1A) receptor antagonistic activity in this postsynaptic structure. These properties of WF-516 define the transporter/receptorial profile of an antidepressant with superior effectiveness.
Assuntos
Antidepressivos/farmacologia , Oxidiazóis/farmacologia , Piperidinas/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina , Animais , Antidepressivos/administração & dosagem , Relação Dose-Resposta a Droga , Eletrofisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Injeções Intravenosas , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Microeletrodos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxidiazóis/administração & dosagem , Piperidinas/administração & dosagem , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismoRESUMO
Duloxetine is a dual inhibitor of norepinephrine (NE) and serotonin (5-HT) uptake. Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant. The aim of this study was to assess the effects of duloxetine on the 5-HT and NE reuptake processes in healthy human volunteers. Twenty-seven healthy young males without a history of psychiatric disorder were randomly assigned to four groups, each group receiving one of the following daily drug regimens: placebo, clomipramine (a potent 5-HT/NE reuptake blocker) 100 mg/day, duloxetine 20 mg/day, or duloxetine 60 mg/day. In order to assess the NE reuptake process, the pressor response to intravenous tyramine (4 and 6 mg) was measured. Determination of the whole blood 5-HT content was used to evaluate the 5-HT reuptake blockade. These measurements were performed at baseline and repeated after 7 and 14 days of drug intake. Both duloxetine, at doses of 20 to 60 mg/day, and clomipramine significantly interfered with the 5-HT reuptake process, as demonstrated by marked decreases in blood 5-HT concentrations. However, the same doses of duloxetine, unlike clomipramine, failed to impede the usual increase in blood pressure that follows a tyramine intravenous infusion, indicating that clomipramine but not duloxetine blocked NE reuptake. At doses tested in a population of healthy volunteers, duloxetine acted as a selective 5-HT reuptake inhibitor, having no clear effect on the NE reuptake process. Nevertheless, given that the highest dose of duloxetine increased supine systolic blood pressure, it is possible that it represents the threshold regimen for NE reuptake inhibition.
Assuntos
Inibidores da Captação Adrenérgica/administração & dosagem , Química Encefálica/efeitos dos fármacos , Depressão/tratamento farmacológico , Norepinefrina/sangue , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Serotonina/metabolismo , Tiofenos/administração & dosagem , Adolescente , Inibidores da Captação Adrenérgica/efeitos adversos , Inibidores da Captação Adrenérgica/farmacocinética , Adulto , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Química Encefálica/fisiologia , Clomipramina/administração & dosagem , Clomipramina/efeitos adversos , Clomipramina/farmacocinética , Depressão/metabolismo , Depressão/fisiopatologia , Relação Dose-Resposta a Droga , Cloridrato de Duloxetina , Humanos , Masculino , Valores de Referência , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Tiofenos/efeitos adversos , Tiofenos/farmacocinética , Tiramina/administração & dosagem , Tiramina/efeitos adversos , Tiramina/farmacocinéticaRESUMO
YM992 is a selective serotonin (5-HT) reuptake inhibitor and a 5-HT(2A) antagonist with potential antidepressant activity. As expected from a 5-HT reuptake inhibitor, which induces an accumulation of 5-HT in the dorsal raphe, YM992 inhibited the firing activity of these 5-HT neurons (ED50: 2.0+/-0.2 mg/kg, i.v.). This effect was reversed by the 5-HT(1A) antagonist WAY 100635. YM992 also dose-dependently prolonged the time for CA3 neurons to recover 50% of their firing rate following microiontophoretic applications of 5-HT, a reliable index of the function of the 5-HT reuptake carrier. In a second series of experiments, the adaptative properties of 5-HT neurons were examined during sustained administration of YM992 (20 mg/kg/day, s.c., delivered by osmotic minipumps) after 2 days of treatment. YM992 decreased by more than 60% the firing activity of the 5-HT neurons. There was a partial recovery of firing after 7 days and a complete one after 14 days of treatment in the presence of the minipump still delivering the drug. In a third series of experiments, the sensitivity of pre- and postsynaptic 5-HT(1A) receptors in the dorsal raphe and the dorsal hippocampus were assessed. The results showed that YM992 attenuated the inhibitory effect of intravenous administration of LSD and the 5-HT(1A) agonist 8-OH-DPAT on the firing activity of 5-HT neurons. As did the selective 5-HT reuptake inhibitor fluvoxamine, YM992 markedly increased the effectiveness of the electrical stimulation of ascending 5-HT fibres on firing activity of the postsynaptic hippocampus pyramidal neurons. This enhancement of 5-HT neurotransmission by YM992 was attributable to a desensitization of the terminal 5-HT(1B) autoreceptors since the postsynaptic 5-HT(1A) receptors in the hippocampus remained normosensitive.
Assuntos
Hipocampo/efeitos dos fármacos , Morfolinas/farmacologia , Neurônios/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/antagonistas & inibidores , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Estimulação Elétrica , Fluvoxamina/farmacologia , Hipocampo/citologia , Hipocampo/metabolismo , Injeções Intravenosas , Dietilamida do Ácido Lisérgico/administração & dosagem , Dietilamida do Ácido Lisérgico/antagonistas & inibidores , Dietilamida do Ácido Lisérgico/farmacologia , Masculino , Morfolinas/administração & dosagem , Morfolinas/antagonistas & inibidores , Neurônios/metabolismo , Piperazinas/farmacologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Piridinas/farmacologia , Núcleos da Rafe/citologia , Núcleos da Rafe/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/antagonistas & inibidores , Transmissão Sináptica/efeitos dos fármacosRESUMO
Flibanserin (BIMT 17) has been described as a 5-HT1A agonist with preferential affinity for postsynaptic 5-HT1A receptors and as a 5-HT2A antagonist. Indeed, using the forskolin-stimulated cAMP accumulation technique, flibanserin but not the 5-HT1A agonists buspirone and 8-OH-DPAT had agonistic activity at postsynaptic 5-HT1A receptors in the cerebral cortex. The present in vivo electrophysiological study investigated the agonistic properties of this novel compound in pre- and postsynaptic areas of the anesthetized rat brain using local microiontophoretic application and systemic administration. The inhibition induced by either local or intravenous administration of flibanserin was current- and dose-dependent. Based on the ability of 5-HT1A antagonists to block or reverse the inhibitory action of the compound, the effect of flibanserin was shown to be mediated via 5-HT1A receptors. In addition, as determined by the concurrent microiontophoretic application of flibanserin and 5-HT, flibanserin behaved as a full agonist in the dorsal raphe nucleus (DRN) and the medial prefrontal cortex (mPFC), but as a partial agonist in the CA3 region of the hippocampus. Based on neuronal responsiveness observed with the local microiontophoretic application of flibanserin, it was found that the agonist was most potent on 5-HT1A receptors in the hippocampus, followed by the mPFC and DRN (I.T50 values: 260, 1,260, and 1,365 nanocoulombs, respectively). However, based on the ED50 values obtained from intravenous administration of the drug, flibanserin was most potent in the DRN followed by the hippocampus and mPFC (ED50 values: 239, 1,414, and 2,984 micrograms/kg, respectively). Therefore, flibanserin presented a marked selectivity for postsynaptic 5-HT1A receptors when applied locally, but not when administered intravenously. It remains to be determined if flibanserin preferentially activates postsynaptic 5-HT1A receptors upon sustained systemic administration.
Assuntos
Benzimidazóis/farmacologia , Encéfalo/metabolismo , Terminações Pré-Sinápticas/metabolismo , Receptores de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Sinapses/metabolismo , Animais , Benzimidazóis/administração & dosagem , Encéfalo/citologia , Eletrofisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Injeções Intravenosas , Iontoforese , Masculino , Neurônios/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Núcleos da Rafe/citologia , Núcleos da Rafe/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/efeitos dos fármacos , Serotonina/farmacologia , Agonistas do Receptor de Serotonina/administração & dosagemRESUMO
The intravenous administration of low doses of lysergic acid diethylamide (LSD) or of the selective 5-hydroxytryptamine1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) depresses the firing activity of dorsal raphe 5-HT-containing neurons, presumably via the activation of 5-HT1A receptors. The present studies were undertaken to determine the effect of different types of 5-HT receptor antagonists on this effect of LSD and 8-OH-DPAT. (-)-Propranolol (2 mg/kg i.v.), methiothepin (2 mg/kg i.p., twice daily for 4 days followed by an additional dose of 2 mg/kg i.p., prior to the experiment), pelanserine (0.5 mg/kg i.v.), and indorenate (125 micrograms/kg i.v.) failed to block the effects of either LSD or 8-OH-DPAT on the firing activity of 5-HT neurons of the dorsal raphe nucleus. However, spiperone (1 mg/kg i.v.) significantly reduced the effect of both LSD and 8-OH-DPAT. These results indicate that, among the five putative 5-HT receptor antagonists tested, only spiperone can antagonize the suppressant effect of 5-HT receptor agonists on the firing of dorsal raphe 5-HT neurons.
Assuntos
Neurônios/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , 5-Metoxitriptamina/análogos & derivados , 5-Metoxitriptamina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina , Animais , Eletrofisiologia , Dietilamida do Ácido Lisérgico/farmacologia , Masculino , Metiotepina/farmacologia , Neurônios/fisiologia , Propranolol/farmacologia , Quinazolinas/farmacologia , Núcleos da Rafe/citologia , Núcleos da Rafe/fisiologia , Ratos , Ratos Endogâmicos , Espiperona/farmacologia , Tetra-Hidronaftalenos/farmacologiaRESUMO
The efficacy of serotoninergic (5-HT) neurotransmission was assessed in the rat brain following different types of antidepressant treatments. First, the firing rate of 5-HT neurons was assessed. Second, the responsiveness of postsynaptic neurons to 5-HT was evaluated by applying directly onto these neurons the neurotransmitter by microiontophoresis. Finally, the effect of the electrical stimulation of the 5-HT pathway on the firing activity of the same postsynaptic neurons was studied in order to determine the efficacy of synaptic transmission. Long-term administration of tricyclic antidepressant drugs induces a sensitization of rat forebrain neurons to 5-HT without altering 5-HT neuron properties. This sensitization results in an enhancement of the effect of the stimulation of the 5-HT pathway on the firing activity of postsynaptic neurons. Long-term administration of antidepressant monoamine oxidase inhibitors also results in an enhancement of the effectiveness of the stimulation of the 5-HT pathway. This is not due to a modification of postsynaptic neuron properties, since there is no enhancement of their responsiveness to 5-HT. Furthermore, the function of the terminal 5-HT autoreceptor is not altered by long-term treatment with a monoamine oxidase inhibitor. Therefore, the enhancement of 5-HT neurotransmission produced by this type of drugs is due to an increased availability of releasable 5-HT. The acute administration of 5-HT reuptake blockers does not enhance the efficacy of the stimulation of the 5-HT pathway. However, their long-term administration produces such an enhancement without altering the responsiveness of postsynaptic neurons to 5-HT. This modification of 5-HT transmission is attributable to a desensitization of the terminal 5-HT autoreceptor, thereby allowing a greater amount of 5-HT to be released per impulse in the synaptic cleft. The electrophysiological assessment of the effects of these different types of antidepressant treatments on the 5-HT system therefore revealed as a common effect an enhancement of 5-HT neurotransmission, albeit each one achieving this via a different mechanism.