RESUMO
The purpose of this study was to evaluate the safety and pharmacokinetics of nemifitide, a synthetic antidepressant pentapeptide, following its subcutaneous (s.c.) administration by standard needle injection or by a needle-free (Biojecttrade mark) injection and to compare these two routes of administration for systemic exposure. This small-scale, randomized, single-dose, parallel design, open-label pilot study consisted of three treatment groups of four subjects each dosed as follows: group 1: 40 mg of nemifitide administered by standard needle/syringe and groups 2 and 3: 40 and 80 mg nemifitide, respectively, administered by using a needle-free (Bioject injection delivery system. Plasma concentrations of nemifitide were determined by LC/MS/MS in blood samples collected at 10 min and 0.5, 1, 2, 4, 6 and 24 h after dosing. PK parameters, including observed C(max), T(max) and AUC(0-24), were calculated and statistical analysis of the data was conducted. Safety assessments (dosing site evaluations) were done at 0.5, 1, 5 and 24 h after dosing. Vital signs and clinical laboratory tests were taken on day 1 prior to dosing and at 24 h post-dose. Adverse experiences in all subjects were observed only as drug-related local reactions at the injection sites. All were considered mild in severity and transient (resolved by 24 h after dosing). T(max) was observed at 10 min after dose and was the same in all subjects. In the three dosing groups, 1 (40 mg), 2 (40 mg) and 3 (80 mg), observed C(max) values were 226, 245 and 440 ng/ml, respectively, and AUC(0-24) values were 108, 106 and 205 ng.h/ml, respectively. Ratios of AUC(0-24) and observed C(max) for nemifitide in plasma between groups 1 and 2 were within the 80%-125% range, indicating that the two modes of drug administration resulted in similar systemic exposure to nemifitide. Pharmacokinetic parameters (AUC(0-24) and C(max)) indicate dose-proportionality between the doses of 40 and 80 mg.
Assuntos
Antidepressivos/farmacocinética , Oligopeptídeos/farmacocinética , Adulto , Idoso , Antidepressivos/administração & dosagem , Antidepressivos/sangue , Área Sob a Curva , Feminino , Humanos , Injeções Subcutâneas/métodos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Oligopeptídeos/sangue , Projetos PilotoRESUMO
This study was designed to determine the safety, efficacy and pharmacokinetics of the antidepressant netamiftide (previously designated name: INN 00835) after 5 or 10 daily doses administered to patients diagnosed with major depression. Netamiftide was administered subcutaneously at a fixed dose of 18 mg/patient per day. Of the 55 enrolled patients, 22 were dosed for 10 days with drug, 11 for 5 days with drug followed by 5 days with placebo and 22 for 10 days with placebo only. The effect of treatment with netamiftide was evaluated by the following psychometric tests: Hamilton Depression Rating, Montgomery-Asberg Depression Rating Scale, Carroll Self-Rating Depression and Clinical Global Impression scales. None of the patients experienced significant adverse effects. A pharmacodynamic correlation (P < 0.05) was found between plasma drug concentrations and response to treatment. Highest plasma concentrations (Cmax) of netamiftide averaging 45.7 ng/ml were observed at 0.25 h after dosing. There were 89% responders in the group with Cmax > or = 45.7 ng/ml (minimum therapeutic concentration) versus 40% in the group with Cmax < 45.7 ng/ml. Onset of action was observed within 48 h after treatment, peak effect was observed at approximately 1 week after treatment and efficacy lasted during a 4-week follow-up period. Netamiftide is a promising antidepressant with rapid onset of action and with an excellent safety profile.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Adolescente , Adulto , Idoso , Antidepressivos/efeitos adversos , Antidepressivos/sangue , Transtorno Depressivo/psicologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Oligopeptídeos/sangue , Pacientes Ambulatoriais , Projetos Piloto , Escalas de Graduação PsiquiátricaRESUMO
BACKGROUND: We assessed the tolerability and utility of switching fluoxetine nonresponders to citalopram the day that fluoxetine therapy was stopped. METHOD: Fifty-eight outpatients with DSM-IV major depressive episode and prospectively confirmed nonresponse to fluoxetine (mean final dose = 31 mg/day) were switched directly to citalopram (20 mg/day). Of the 58 patients, 44 (76%) had never been successfully treated with antidepressant medication. During a 12-week open-label treatment period, citalopram could be titrated up to a maximum dose of 60 mg/day. Response was evaluated using the Clinical Global Impressions (CGI) scale, the 24-item Hamilton Rating Scale for Depression, and several other measures. RESULTS: Eighty-one percent (N = 47) completed the trial, and citalopram (mean dose = 38.8 mg/day) was well tolerated. The intent-to-treat CGI response rate was 46% (26/57) at week 6 and 63% (36/57) at study endpoint; the completer response rate was 76% among the 47 patients who completed the 12-week trial. Improvement from baseline on all dependent measures was statistically significant after the first week of citalopram treatment. CONCLUSION: Fluoxetine nonresponders can be quickly switched to citalopram, with good tolerability and reasonable chance of therapeutic benefit. Further work is necessary to assess the merits of this treatment strategy relative to other options.
Assuntos
Citalopram/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Fluoxetina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adulto , Assistência Ambulatorial , Citalopram/administração & dosagem , Transtorno Depressivo/psicologia , Esquema de Medicação , Feminino , Fluoxetina/administração & dosagem , Humanos , Masculino , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
BACKGROUND: INN 00835 is a synthetic pentapeptide with a potential for rapid onset of action as an antidepressant. Its efficacy was investigated in a pilot study in patients diagnosed with major depression. METHODS: Fifty two patients received either active drug - INN 00835 (26 patients) - or placebo (26 patients), subcutaneously at 0.2 mg/kg for 5 consecutive days. The patients were evaluated for an additional 4 weeks after treatment. Efficacy was evaluated by the following psychiatric rating scales: HAMD, MADRS, CSRS, CGI, and VAS. The effect of treatment was also evaluated by using a biochemical marker: changes in blood platelet serotonin (5HT) uptake rates in drug-treated patients compared to those in the placebo group. Plasma concentrations of INN 00835 were measured by LC/MS. RESULTS: Statistical analysis indicated a strong pharmacodynamic correlation between plasma drug concentrations at 1 h after dosing and the reduction in the severity of depression as measured by the psychiatric rating scales. A minimum effective plasma concentration (MEC) of INN 00835 was 5 ng/ml. Statistically significant differences in response to treatment (P<0.05) were found between patients with plasma concentrations above MEC and those in the placebo group, as well as between subjects with plasma concentrations above and below the MEC. The peak effect was observed after the 5-day treatment and the response to treatment persisted during the 4-week follow-up period. The change of 5HT uptake rates after treatment was significantly larger in the drug-treated group than in the placebo group. LIMITATIONS: This was a pilot study conducted in a relatively small population (52 patients) and the limited number of blood sampling times did not allow a comprehensive pharmacokinetic analysis. There was a relatively large placebo response. The results have to be confirmed in future, large scale studies. CONCLUSIONS: INN 00835 appears to be a promising drug for the treatment of major depression.
Assuntos
Antidepressivos/farmacocinética , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Oligopeptídeos/farmacocinética , Oligopeptídeos/uso terapêutico , Adulto , Antidepressivos/sangue , Biomarcadores , Transtorno Depressivo Maior/diagnóstico , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/sangue , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Serotonina/metabolismo , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The psychopharmacology of depression is a field that has evolved rapidly in just under 5 decades. Early antidepressant medications--tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)--were discovered through astute clinical observations. These first-generation medications were effective because they enhanced serotonergic or noradrenergic mechanisms or both. Unfortunately, the TCAs also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this action brought about unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. MAOIs can interact with tyramine to cause potentially lethal hypertension and present potentially dangerous interactions with a number of medications and over-the-counter drugs. The newest generation of antidepressants, including the single-receptor selective serotonin reuptake inhibitors (SSRIs) and multiple-receptor antidepressants venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone, target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. This paper discusses the new antidepressants, particularly with regard to mechanism of action, and looks at future developments in the treatment of depression.
Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Antidepressivos/uso terapêutico , Antidepressivos Tricíclicos/história , Antidepressivos Tricíclicos/farmacologia , Antidepressivos Tricíclicos/uso terapêutico , Cicloexanóis/farmacologia , Cicloexanóis/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , História do Século XX , Humanos , Inibidores da Monoaminoxidase/história , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Cloridrato de VenlafaxinaRESUMO
The syndromes of anxiety and depression may reflect separate disorders with overlapping symptoms. They also may be comorbid or reflect illnesses with similar underlying pathophysiology based upon a spectrum of central nervous system dysfunction. Antidepressants effectively treat both anxiety and comorbid anxiety-depression. Tertiary tricyclic antidepressant agents (TCAs) with dual serotonergic-noradrenergic effects, such as imipramine and amitriptyline, appear consistently effective across the anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are particularly effective in panic disorder and obsessive-compulsive disorder. SSRIs are similar in efficacy to TCAs but are more tolerable and cause fewer serious adverse events. However, they are relatively slow to act, and efficacy data are limited in states such as generalized anxiety disorder. Newer antidepressants, such as mirtazapine, nefazodone, and venlafaxine XR, may provide some benefits across the broad spectrum of anxiety disorders with the safety and tolerability that are the hallmarks of third generation antidepressants.
Assuntos
Antidepressivos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Antidepressivos Tricíclicos/uso terapêutico , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/psicologia , Comorbidade , Cicloexanóis/uso terapêutico , Preparações de Ação Retardada , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/psicologia , Humanos , Inibidores da Monoaminoxidase/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Cloridrato de VenlafaxinaRESUMO
BACKGROUND: INN 00835 (4-fluoro-L-phenylalanyl-trans-4-hydroxy-L-prolyl-L-arginyl-glycyl-trypt ophanamide ditrifluoroacetate) is a synthetic pentapeptide antidepressant with a potential for rapid onset of action. We were interested to see if such action could be correlated with serotonin uptake by platelets. METHODS: In a phase II clinical trial, unipolar depressed patients were administered active drug, INN 00835 or placebo, subcutaneously, at 0.2 mg/kg, once daily for 5 consecutive days. Efficacy of treatment was evaluated by psychometric tests (HAMD, MADS, CSRS, CGI and total VAS). Changes in platelet uptake rates of serotonin (3H-5HT) were measured in plasma from the patients participating in the phase II clinical trial, prior to and immediately after treatment with INN 00835 (19 patients) or placebo (16 patients), to evaluate the effect of treatment with INN 00835 on the rate of platelet 5-HT uptake. RESULTS: The data evaluated by using the psychometric tests indicated a significant response to treatment with INN 00835 after 5 days of dosing. The rates of platelet 5-HT uptake were lower prior to treatment (baseline), and increased after the 5-day treatment period. The change in the uptake rate (deltaVmax) following treatment was significantly larger in the active group than in the placebo group (P < 0.05). The difference between the placebo group and the patients who responded to treatment was even larger. LIMITATIONS: Small number of subjects. CONCLUSION: The data tend to substantiate the use of platelet serotonin uptake as a biochemical marker of effective treatment of depression.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Serotonina/metabolismo , Adulto , Antidepressivos/farmacologia , Plaquetas/fisiologia , Transtorno Depressivo/fisiopatologia , Método Duplo-Cego , Humanos , Injeções Subcutâneas , Oligopeptídeos/farmacologia , Psicometria , Resultado do TratamentoRESUMO
BACKGROUND: Citalopram, the most selective serotonin reuptake inhibitor (SSRI), is a bicyclic phthalane derivative with a chemical structure that is unrelated to that of other SSRIs and available antidepressants. The drug is approved for use in 69 countries. This 6-week, fixed-dose, placebo-controlled, parallel-arm, multicenter trial was performed to confirm its efficacy and safety in treatment of outpatients with major depression in the United States. METHOD: Six hundred and fifty adult outpatients with moderate-to-severe major depression (DSM-III-R) were randomly assigned to receive citalopram at doses of 10 mg (N = 131), 20 mg (N = 130), 40 mg (N = 131), or 60 mg (N = 129) or placebo (N = 129) once daily. Outcome assessments were the 21-item Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions scale. RESULTS: Between-group comparisons of the change from baseline to endpoint revealed significantly greater improvement in the citalopram patients relative to the placebo patients on all 3 efficacy measures. Patients randomly assigned to 40 mg/day and 60 mg/day of citalopram showed significantly greater improvement than placebo on all efficacy measures, as well as on the HAM-D symptom clusters measuring depressed mood, melancholia, cognitive disturbance, and psychomotor retardation. Patients who received 10 mg/day and 20 mg/day of citalopram also showed consistent improvement relative to placebo on all efficacy ratings, with statistical significance demonstrated in the MADRS response rate, the HAM-D depressed mood item, and the HAM-D melancholia subscale. Citalopram was well tolerated, with only 15% of patients discontinuing for adverse events. The side effects most commonly associated with citalopram treatment were nausea, dry mouth, somnolence, insomnia, and increased sweating. CONCLUSION: Citalopram was significantly more effective than placebo in the treatment of moderate-to-severe major depression, especially symptoms of depressed mood and melancholia, with particularly robust effects shown at doses of 40 and 60 mg/day. Citalopram was well tolerated in spite of forced upward titration to fixed-dose levels, with a low incidence of anxiety, agitation, and nervousness.
Assuntos
Citalopram/administração & dosagem , Transtorno Depressivo/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Administração Oral , Adulto , Assistência Ambulatorial , Citalopram/efeitos adversos , Citalopram/uso terapêutico , Transtorno Depressivo/psicologia , Esquema de Medicação , Feminino , Cefaleia/induzido quimicamente , Humanos , Masculino , Náusea/induzido quimicamente , Placebos , Escalas de Graduação Psiquiátrica , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Índice de Gravidade de Doença , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Resultado do TratamentoRESUMO
BACKGROUND: We examined the efficacy and safety of three different dosages of venlafaxine hydrochloride (75, 225, and 375 mg/day) in a multicenter, randomized, double-blind, placebo-controlled, four-group study. METHOD: Outpatients, 18 to 65 years old, who met DSM-III criteria for major depression were included (N = 358 randomized; 194 completed). Of the total patients completing the trial, 59%, 56%, 51%, and 51% were in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. The primary outcome measures were the Hamilton Rating Scale for Depression (HAM-D21) total, HAM-D21 depression item, Montgomery-Asberg Depression Rating Scale total, and Clinical Global Impressions scale. RESULTS: Each dosage of venlafaxine was associated with statistically significant improvement as compared with placebo, based on the intent-to-treat sample. The two higher dosages were associated with a modestly greater antidepressant response than was the 75-mg dosage. Nausea, dizziness, somnolence, and anorexia were the most common adverse events attributable to venlafaxine. Since headache occurred at a similar frequency in both the drug and placebo groups, we did not consider it to be attributable to venlafaxine use. Withdrawal from the study due to adverse events occurred in 5%, 17%, 24%, and 30% of the patients in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. CONCLUSION: Venlafaxine, at dosages of 75-375 mg/day, is an effective and well-tolerated antidepressant. With increasing dosage, greater efficacy and possibly more adverse effects will occur.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Cicloexanóis/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Adulto , Idoso , Assistência Ambulatorial , Anorexia/induzido quimicamente , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/efeitos adversos , Cicloexanóis/administração & dosagem , Cicloexanóis/efeitos adversos , Transtorno Depressivo/psicologia , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Placebos , Escalas de Graduação Psiquiátrica , Transtornos do Sono-Vigília/induzido quimicamente , Resultado do Tratamento , Cloridrato de VenlafaxinaRESUMO
The effects of once-daily venlafaxine extended release (XR) 75-225 mg/day on symptoms of anxiety in depressed outpatients were assessed in two randomized, double-blind, placebo-controlled trials. In study 1, venlafaxine XR was significantly (p < or = 0.05) more effective than placebo by week 4 in relieving anxiety symptoms among patients with moderate or greater anxiety (anxiety-psychic item score > or = 2) at baseline. Among patients with severe (anxiety-psychic item score > or = 3) anxiety, venlafaxine XR was significantly (p < or = 0.05) more effective than placebo beginning at week 6. In study 2, among patients with moderate or greater anxiety (score > or = 2) at baseline, a significant reduction (p < or = 0.05- < or = 0.001) in HAM-D anxiety-psychic item scores was noted with venlafaxine XR compared with placebo from weeks 1 to 8. Among patients with severe anxiety (score > or = 3) at baseline, venlafaxine XR produced a significant reduction (p < or = 0.05- < or = 0.001) in the anxiety-psychic item score compared with placebo from weeks 1 to 8. Discontinuation for adverse events occurred in 11% of patients on venlafaxine XR, and the most common adverse events were nausea, dizziness, insomnia, somnolence and dry mouth. These results indicate that once-daily venlafaxine XR is effective for the treatment of anxiety symptoms associated with major depression in doses ranging from 75 to 225 mg/day.
Assuntos
Assistência Ambulatorial , Antidepressivos de Segunda Geração/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Cicloexanóis/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Adulto , Antidepressivos de Segunda Geração/administração & dosagem , Transtornos de Ansiedade/epidemiologia , Estudos de Coortes , Comorbidade , Cicloexanóis/administração & dosagem , Preparações de Ação Retardada , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/psicologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Placebos , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Resultado do Tratamento , Cloridrato de VenlafaxinaRESUMO
BACKGROUND: Cardiovascular side effects from antidepressant drugs, including clinically significant blood pressure changes, conduction disturbances, and arrhythmias may complicate long-term therapy. Cardiovascular effects are most common with tricyclic antidepressants, but occur rarely with most antidepressants. Venlafaxine is a unique antidepressant with a broad spectrum of antidepressant activity and a safety profile that resembles serotonin selective reuptake inhibitors. METHOD: A MEDLINE search of the literature in the English language for the past 15 years was conducted, and the venlafaxine new drug application data base was reviewed. RESULTS: Clinically significant conduction abnormalities or arrhythmias have not been reported with venlafaxine; however, this drug has not been studied in patients with underlying cardiovascular disease. A dose-related increase in mean blood pressure has been observed. In placebo-controlled studies with venlafaxine, clinically significant increases in blood pressure (increase in diastolic blood pressure of > or = 15 mm Hg and to > or = 105 mm Hg from baseline) were observed in 5.5% of patients at doses above 200 mg daily. The mean increase in diastolic blood pressure was 7 mm Hg after 6 weeks of treatment with doses of 300 to 375 mg daily. In comparative trials, the overall incidence of clinically significant blood pressure increases with venlafaxine was similar to that of tricyclic antidepressants. CONCLUSION: Overall, venlafaxine has a low incidence of clinically significant increases in blood pressure at doses below 200 mg daily. As with other antidepressants that may affect blood pressure, the clinician should periodically monitor blood pressure in patients treated with venlafaxine.
Assuntos
Arritmias Cardíacas/induzido quimicamente , Cicloexanóis/efeitos adversos , Transtorno Depressivo/tratamento farmacológico , Hipertensão/induzido quimicamente , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Antidepressivos Tricíclicos/efeitos adversos , Antidepressivos Tricíclicos/uso terapêutico , Arritmias Cardíacas/epidemiologia , Pressão Sanguínea/efeitos dos fármacos , Ensaios Clínicos como Assunto , Cicloexanóis/uso terapêutico , Transtorno Depressivo/psicologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Sistema de Condução Cardíaco/efeitos dos fármacos , Humanos , Hipertensão/epidemiologia , Hipotensão Ortostática/induzido quimicamente , Hipotensão Ortostática/epidemiologia , Incidência , Placebos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Cloridrato de VenlafaxinaRESUMO
BACKGROUND: The mechanism of action of the novel antidepressant bupropion remains unclear after many years of study. A review of the relevant biochemical, in vivo brain microdialysis, electrophysiologic, behavioral, and clinical data clarifies what is known about this unique compound and suggests possible modes of action. METHOD: A panel of 11 experts was convened for a conference to discuss bupropion's mechanism of antidepressant activity. Four of the panelists presented current research findings, followed by a discussion. RESULTS: (1) Biochemical studies suggest down-regulation of postsynaptic beta-adrenoceptors and desensitization of the norepinephrine-stimulated adenylate cyclase in the rat cortex occur only after chronic administration of very high doses of bupropion. (2) In vivo brain microdialysis studies demonstrate that, after chronic administration, there is an enhancement of bupropion-induced increases in extracellular dopamine in the nucleus accumbens. (3) Electrophysiologic data show that with acute dosing, bupropion reduces the firing rates of noradrenergic neurons in the locus ceruleus. The firing rates of dopaminergic neurons are reduced by bupropion in the A9 and A10 areas of the brain, but only at very high doses, and bupropion does not alter the firing rates of serotonergic neurons in the dorsal raphe. (4) Behavioral studies show that the most active metabolite of bupropion, hydroxybupropion (306U73), appears to be responsible for a large part of the compound's effects in animal models of antidepressant activity. (5) Clinical studies indicate that bupropion enhances noradrenergic functional activity as reflected by an increased excretion of the hydroxy metabolite of melatonin, while at the same time producing a presumably compensatory decrease in norepinephrine turnover. In one study, bupropion elevated plasma levels of the dopamine metabolite homovanillic acid in nonresponders, but not in responders. CONCLUSION: The mechanism of action of bupropion appears to have an unusual, not fully understood, noradrenergic link. The bupropion metabolite hydroxybupropion probably plays a critical role in bupropion's antidepressant activity, which appears to be predominantly associated with long-term noradrenergic effects. The mild central nervous system activating effects of bupropion appear to be due to weak dopaminergic mechanisms. There is some evidence that dopamine may contribute to bupropion's antidepressant properties. Antidepressant effects of bupropion are not serotonergically mediated.
Assuntos
Antidepressivos/farmacologia , Bupropiona/farmacologia , Animais , Antidepressivos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bupropiona/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/psicologia , Dopamina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Locus Cerúleo/efeitos dos fármacos , Camundongos , Microdiálise , Neurônios/efeitos dos fármacos , Norepinefrina/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Ratos , Receptores Adrenérgicos beta/efeitos dos fármacos , Serotonina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Resultado do TratamentoRESUMO
A simulation decision analytical model was used to compare the annual direct medical costs of treating patients with major depression using the selective serotonin reuptake inhibitor (SSRI) paroxetine or the tricyclic antidepressant (TCA) imipramine. Medical treatment patterns were determined from focus groups of general and family practitioners and psychiatrists in Boston, Dallas and Chicago, US. Direct medical costs included the wholesale drug acquisition costs (based on a 6-month course of drug therapy), psychiatrist and/or general practitioner visits, hospital outpatient visits, hospitalisation and electroconvulsive therapy. Acute phase treatment failure rates were derived from an intention-to-treat analysis of a previously published trial of paroxetine, imipramine and placebo in patients with major depression. Maintenance phase relapse rates were obtained from a 12-month trial of paroxetine, supplemented from the medical literature. The relapse rates for the final 6 months of the year were obtained from medical literature and expert opinion. Direct medical costs were estimated from a health insurance claims database. The estimated total direct medical cost per patient was slightly lower using paroxetine ($US2348) than generic imipramine ($US2448) as first-line therapy. This result was sensitive to short term dropout rates but robust to changes in other major parameters, including hospitalisation costs and relapse rates. The financial benefit of paroxetine, despite its 15-fold higher acquisition cost compared with imipramine, is attributable to a higher rate of completion of the initial course of therapy and consequent reduced hospitalisation rates.
Assuntos
Antidepressivos de Segunda Geração/economia , Antidepressivos de Segunda Geração/uso terapêutico , Antidepressivos Tricíclicos/economia , Antidepressivos Tricíclicos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/economia , Imipramina/economia , Imipramina/uso terapêutico , Paroxetina/economia , Paroxetina/uso terapêutico , Simulação por Computador , Custos e Análise de Custo , Transtorno Depressivo/psicologia , Humanos , Reembolso de Seguro de Saúde , Modelos Econômicos , Pacientes Desistentes do Tratamento , Recidiva , Falha de Tratamento , Estados UnidosRESUMO
The purpose of this study is to evaluate the novel antidepressant venlafaxine for the management of treatment-resistant unipolar depression. We gave unblinded venlafaxine to 84 consecutive outpatients and inpatients who met DSM-III-R criteria for major depression and who had failed to respond to at least three adequate trials of antidepressants from at least two different antidepressant classes or electroconvulsive therapy, plus at least one attempt at augmentation. Patients were evaluated after a drug free period at baseline and regular intervals with the 21-item Hamilton Rating Scale for Depression (HAM-D-21), Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions Scale Improvement item (CGI). Full response for each scale was defined as follows: HAM-D-21 score of 8 or lower, a MADRS score of 12 or lower, and CGI score of 1; partial responses was defined as a 50% decrease in the HAM-D and MADRS, with final scores greater than 8 and 12, respectively, and for the CGI, a score equal to 2. About a third of patients were considered to be either full or partial responders (32.9% by HAM-D-21, 30.0% by MADRS, and 40% by CGI) after 12 weeks of venlafaxine treatment. To date, about 46% of responders have sustained their response for at least 3 months after the acute response. Venlafaxine is effective for a significant, but small, minority of patients with rigorously defined triple-resistant depression; the improvement was maintained for about half of the responders for the first 3 months of maintenance therapy.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Cicloexanóis/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Adulto , Idoso , Antidepressivos de Segunda Geração/efeitos adversos , Cicloexanóis/efeitos adversos , Transtorno Depressivo/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Determinação da Personalidade , Inventário de Personalidade , Resultado do Tratamento , Cloridrato de VenlafaxinaRESUMO
The antidepressant venlafaxine has a unique chemical structure and neuropharmacologic profile. It significantly inhibits reuptake of both serotonin and norepinephrine and lacks notable muscarinic-cholinergic or alpha-adrenergic effects. Premarketing studies involving more than 2000 patients showed the efficacy of venlafaxine to be significantly greater than placebo at dosages between 75 and 375 mg/day in both outpatients and inpatients. The medication may be administered twice or three times daily. Venlafaxine was found equally effective for patients older and younger than 60 years and in those with psychomotor retardation or agitation; it proved slightly more efficacious than fluoxetine in a comparison study with melancholic inpatients. A promising finding of these studies is the suggestion of a rapid onset of clinical effect for venlafaxine. In some studies, venlafaxine showed a consistent and robust clinical superiority over placebo by Week 1, and in the inpatient study involving melancholic patients, the superiority of venlafaxine was demonstrated as early as Day 4. In general, early responses are seen at the higher dosages. Venlafaxine has also shown promise in treating rigorously defined treatment-refractory depression. The adverse effects of venlafaxine that most often led to discontinuation from a clinical study were nausea (6%), somnolence (3%), insomnia (3%), and dizziness (3%). Although nausea was the most common adverse effect overall, it resolved rapidly--within the first 1 to 3 weeks of therapy. Other adverse events with incidences significantly higher than with placebo were dizziness, constipation, sweating, nervousness, and abnormal ejaculation. The seizure rate and potential for cardiac conduction changes or orthostatic hypotension with venlafaxine were comparable with rates seen with the serotonin selective reuptake inhibitors. A small number of patients experienced dose-dependent blood pressure elevation with venlafaxine in premarketing studies (3% to 5% of those receiving < or = 200 mg/day; 7% of those receiving 201-300 mg/day; 13% of those receiving > 300 mg/day vs. 2% receiving placebo). In general, venlafaxine is well tolerated, and its treatment discontinuation rate is similar to those of the newer antidepressants and superior to discontinuation rates with the first-generation agents.
Assuntos
Antidepressivos/uso terapêutico , Cicloexanóis/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Fatores Etários , Idoso , Assistência Ambulatorial , Animais , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Ensaios Clínicos como Assunto , Cicloexanóis/farmacocinética , Cicloexanóis/farmacologia , Transtorno Depressivo/psicologia , Esquema de Medicação , Feminino , Fluoxetina/uso terapêutico , Hospitalização , Humanos , Masculino , Ratos , Receptores de Neurotransmissores/efeitos dos fármacos , Cloridrato de VenlafaxinaRESUMO
The SSRIs are a new class of effective antidepressant agents which have proven efficacy in a wide range of psychiatric applications. They are as effective as the tricyclic antidepressants and are better tolerated. The SSRIs are safe in overdose and have minimal drug interactions, and are suitable for once-daily dosing. Newer members of the class, such as paroxetine, have shorter half-lives and no active metabolites, and are likely to be safer than other members of the class. Paroxetine has been compared with the standard tricyclic antidepressants in a range of studies, and the efficacy and tolerability data from these studies have been collected together in the worldwide database on paroxetine. Paroxetine was shown to be at least as effective as active comparators in melancholic depression (DSM-III). In a comparative study of paroxetine and fluoxetine, both drugs were effective in reducing depressive symptoms and paroxetine showed a faster onset of action than fluoxetine. A higher incidence of side-effects was obtained in fluoxetine patients. In a long-term comparative study of paroxetine and placebo, fewer patients relapsed while on paroxetine for one year than on placebo--15 and 38%, respectively.
Assuntos
Depressão/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Fluvoxamina/uso terapêutico , Humanos , Paroxetina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversosRESUMO
The chronic and recurrent nature of major depression is well recognized, and recent data suggest that maintenance therapy with full-dose pharmacotherapy (i.e., the dose used to treat the index episode) is effective in preventing relapse and recurrence. We present results from a 1-year, double-blind trial of paroxetine and imipramine in patients who successfully completed a 6-week acute course of therapy. A total of 717 outpatients were included in the 6-week, randomized, double-blind, placebo-controlled comparative study of paroxetine and imipramine conducted at six centers. At the end of the acute treatment phase, patients showing a therapeutic response were eligible to enter a long-term extension of the study in which they would continue to receive the same drug (or placebo) in double-blind fashion for up to 1 year. Of the 219 patients who entered the long-term phase, 94 received paroxetine, 79 received imipramine, and 46 received placebo. During the 1-year maintenance study, both paroxetine and imipramine were more effective than placebo in maintaining euthymia among patients who had responded to short-term treatment. However, approximately twice as many imipramine-treated patients dropped out of the study prematurely because of adverse experiences compared to paroxetine-treated patients, suggesting that paroxetine is more readily tolerated than imipramine during long-term treatment.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Imipramina/uso terapêutico , Paroxetina/uso terapêutico , Adulto , Idoso , Transtorno Depressivo/psicologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Imipramina/efeitos adversos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Paroxetina/efeitos adversos , Inventário de PersonalidadeRESUMO
These data provide evidence for the antidepressant efficacy of paroxetine. Paroxetine- and imipramine-treated patients were significantly different from placebo-treated patients, but little different to each other, on all depressive outcome measures. However, paroxetine appeared to have a possibly greater and earlier beneficial effect on anxiety symptoms associated with depression, when compared with imipramine. Both active therapies were effective in treating patients with severe depression. Side effects for paroxetine were typical of other serotonin (5-HT) uptake inhibitors but different from those of imipramine. In particular, anticholinergic and cardiovascular symptoms were reduced, and premature withdrawal less likely.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Imipramina/uso terapêutico , Paroxetina/uso terapêutico , Adolescente , Adulto , Idoso , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/psicologia , Transtorno Depressivo/psicologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Imipramina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Paroxetina/efeitos adversos , Inventário de PersonalidadeRESUMO
Ipsapirone is a partial 5-HT1A agonist which appears promising for the pharmacologic treatment of anxiety. In this four-week, double-blind, 19-center study, 249 outpatients with generalized anxiety disorder were randomized to one of four treatments: ipsapirone, 5 or 10 mg t.i.d., diazepam 5 mg t.i.d., or placebo. Both active treatments were significantly superior to placebo in reducing anxiety symptoms, although response to ipsapirone was not significant until week 2 while diazepam had a more rapid onset. Five mg t.i.d. was the optimal ipsapirone dose. At 10 mg t.i.d. adverse experiences prompted more patients to discontinue treatment. Adverse experiences that were reported significantly more often for ipsapirone than placebo included asthenia, nausea, dizziness, paresthesias and sweating. Sedation was the most common diazepam-related side effect. The results of this study when combined with others suggest that 5 mg t.i.d. of ipsapirone is an effective and well-tolerated anxiolytic without many of the risks of benzodiazepine therapy. Dosage escalation by patients is unlikely because of an increased risk of side effects.
Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Diazepam/uso terapêutico , Pirimidinas/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Assistência Ambulatorial , Análise de Variância , Ansiolíticos/administração & dosagem , Ansiolíticos/efeitos adversos , Método Duplo-Cego , Humanos , Testes Psicológicos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/efeitos adversosRESUMO
Diagnostic criteria, random parallel placebo-controlled study design, and appropriate clinical assessment for both safety and efficacy are all among the essential requirements for the evaluation of a new antidepressant agent. Paroxetine and imipramine were compared for efficacy and safety in a large multicentre, randomized, placebo-controlled, double-blind, parallel design study in the USA. The study involved 717 outpatients with major depressive disorder; after a one-week washout period they were treated for 6 weeks, being assessed at weekly intervals. The results from all six participant centres combined showed that both active drugs were statistically superior to placebo by week 2 and that the antidepressant response was significant for both. Paroxetine was better tolerated than imipramine with fewer dropouts from side effects. This combined study clearly indicated that paroxetine was an effective and well-tolerated antidepressant.