piperidines and Depressive-Disorder

Acetylcholinesterase inhibitors (AceI) and memantine might prove useful in bipolar disorder (BD) given their neuroprotective and pro-cognitive effects, as highlighted by several case reports. We aimed to systematically review the efficacy and safety of AceI and memantine across multiple outcome dimensions in BD.. Systematic PubMed and SCOPUS search until 04/17/2015 without language restrictions. Included were randomized controlled trials (RCTs), open label studies and case series of AceI or memantine in BD patients reporting quantitative data on depression, mania, psychotic symptoms, global functioning, or cognitive performance. We summarized results using a best-evidence based synthesis.. Out of 214 hits, 12 studies (RCTs=5, other designs=7, total n=422) were included. Donepezil (studies=5; treated=102 vs. placebo=21): there was strong evidence for no effect on mania and psychotic symptoms; low evidence indicating no effect on depression. Galantamine (studies=3; treated=21 vs. controls=20) (placebo=10, healthy subjects=10): there was strong evidence for no effect on mania; moderate evidence for no effect on depression; low evidence for no effect on global functioning. Memantine (studies=4; treated=152 vs. placebo=88): there was conflicting evidence regarding efficacy for mania, depression and global functioning.. Paucity of RCTs; small sample size studies; heterogeneous design, outcome and patient characteristics.. There is limited but converging evidence of no effect of AceI in BD, and conflicting evidence about memantine in BD. Too few studies of mostly medium/low quality and lacking sufficient numbers of patients in specific mood states, especially mania, contributed data, focusing solely on short-term/medium-term treatment, necessitating additional high-quality research to yield more definite results.

Topics: Adult; Bipolar Disorder; Case-Control Studies; Cholinesterase Inhibitors; Clinical Trials as Topic; Depression; Depressive Disorder; Donepezil; Evidence-Based Medicine; Excitatory Amino Acid Antagonists; Female; Galantamine; Humans; Indans; Male; Memantine; Middle Aged; Piperidines; Psychotic Disorders; Randomized Controlled Trials as Topic; Treatment Outcome

This article presents a brief review and summarizes current therapies for the treatment of chronic obstructive pulmonary disease, major depression, and rheumatoid arthritis. One new pharmaceutical agent is highlighted for each of the topics.

Topics: Anti-Anxiety Agents; Arthritis, Rheumatoid; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Depressive Disorder; Fluticasone; Humans; Nursing Process; Piperazines; Piperidines; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyrimidines; Pyrroles; Sulfides; United States; Vortioxetine

CB(1) receptor antagonists were among the most promising drug targets in the last decade. They have been explored and found to be effective as therapeutic agents for obesity and related cardiometabolic problems; however, use of rimonabant, the first marketed CB(1) receptor antagonist, has been suspended because of its anxiogenic and depressogenic side effects. Because some other antiobesity drugs, like dexfenfluramine or sibutramine, were also suspended, the unmet need for drugs that reduce body weight became enormous. One approach that emerged was the use of CB(1) receptor antagonists that poorly cross the blood brain barrier, the second, the development of neutral antagonists instead of inverse agonists, and the third, use of personalized medicine, namely the selection of the patient population without psychiatric side effects. In this review, we dissect the peripheral and central mechanisms involved in the effects of CB(1) receptor antagonists and argue that central mechanisms are more or less involved in most cardiometabolic therapeutic effects and thus, among patients with unsatisfactory therapeutic response to compounds with peripheral action, centrally acting antagonists may be needed. An analysis of pharmacogenetic factors may help to identify persons who are at no or low risk for psychiatric adverse effects. Here, we present the models and identify molecular mechanisms and receptors involved in the effects of stress-, anxiety- and depression-related neurocircuitries sensitive to CB(1) receptor antagonists, like the serotonergic, noradrenergic and dopaminergic systems, which are not only regulated by CB(1) receptors, but also regulate the synthesis of the endocannabinoid 2-arachidonoyl-glycerol.

Topics: Anti-Obesity Agents; Anxiety Disorders; Depressive Disorder; Humans; Obesity; Piperidines; Precision Medicine; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Both agonists (e.g. Delta(9)-tetrahydrocannabinol, nabilone) and antagonists (e.g. rimonabant, taranabant) of the cannabinoid type-1 (CB(1)) receptor have been explored as therapeutic agents in diverse fields of medicine such as pain management and obesity with associated metabolic dysregulation, respectively. CB(1) receptors are widely distributed in the central nervous system and are involved in the modulation of emotion, stress and habituation responses, behaviours that are thought to be dysregulated in human psychiatric disorders. Accordingly, CB(1) receptor activation may, in some cases, precipitate episodes of psychosis and panic, while its inhibition may lead to behaviours reminiscent of depression and anxiety-related disorders. The present review discusses these side-effects, which have to be taken into account in the therapeutic exploitation of the endocannabinoid system.

Topics: Affect; Animals; Anxiety Disorders; Cannabinoid Receptor Modulators; Depressive Disorder; Dronabinol; Humans; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Experimental evidence has suggested that drugs that enhance cannabinoid type-1 (CB1) receptor activity may induce anxiolytic and antidepressant effects, whilst the opposite has been reported with antagonists. Thus, the objective of the present review is to discuss the potential psychiatric side-effects of CB1 receptor antagonists, such as rimonabant, which has been recently marketed in several countries for the treatment of smoking cessation, obesity and associated metabolic disorders.. Literature searches were performed in PubMed and SciELO databases up to February 2009. The terms searched were 'obesity', 'rimonabant', 'cannabinoids', 'unwanted effects', 'diabetes', 'smoking cessation' and 'side-effects'.. Clinical trials have revealed that rimonabant may promote weight loss in obese patients, although it may also induce symptoms of anxiety and depression.. Patients taking CB1 receptor antagonists should be carefully investigated for psychiatric side-effects. These drugs should not be prescribed for those already suffering from mental disorders. Nevertheless, the development of new compounds targeting the endocannabinoid system for the treatment of several conditions would be necessary and opportune.

Topics: Anxiety Disorders; Appetite Depressants; Cannabinoid Receptor Modulators; Depressive Disorder; Humans; Metabolic Diseases; Obesity; Piperidines; Placebo Effect; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant; Smoking; Smoking Cessation

Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMP

Topics: Adult; Aged; Animals; Benzothiadiazines; Brain-Derived Neurotrophic Factor; Cognition Disorders; Depressive Disorder; Excitatory Amino Acid Agonists; Humans; Neuronal Plasticity; Parkinson Disease; Piperidines; Pyrrolidinones; Receptors, AMPA

The antidepressant activity of monoamine oxidase inhibitors has been well established for 30 years. Nevertheless, this group of compounds was handled with great care, mainly because of the interaction potential with tyramine-containing foodstuff. With the discovery of reversible and selective inhibitors of monoamine oxidase type A a renaissance of these compounds has begun. In this paper one of these new substances--brofaromine--will be described in detail. Biochemical and pharmacological aspects will be reviewed, showing that brofaromine is a selective and reversible inhibitor of monoamine oxidase type A with additional serotonin reuptake inhibiting properties. Both mechanisms of action may synergize in the antidepressant effect of the compound. The main results of clinical trials in depression and other indication areas will also be covered. Special attention will be put on the side effect profile.

Topics: Animals; Brain Chemistry; Depressive Disorder; Humans; Monoamine Oxidase Inhibitors; Piperidines

Antidepressant drugs are effective for about three in four people with depression. For reasons that are not understood, individual patients who do not respond to one drug often respond to another. Differences in mechanisms of action may thus be important in determining treatment success or failure. In addition to efficacy, drug side effect profile also determines treatment outcome. In general, the fewer or less severe the side effects of a drug, the greater the degree of compliance with treatment. A major consequence of the introduction of selective serotonin-specific antidepressants is greater patient acceptance due to fewer side effects. Still, some patients are unable to tolerate the nervousness, insomnia, or sexual dysfunction associated with these drugs. Drugs that are even more specific in that they act on specific serotonin receptor subtypes, rather than only by blocking serotonin uptake, may provide efficacy and fewer side effects for patients who do not respond to or tolerate less specific agents.

Topics: Antidepressive Agents; Buspirone; Depressive Disorder; Humans; Isoxazoles; Ondansetron; Piperazines; Piperidines; Receptors, Serotonin; Risperidone; Selective Serotonin Reuptake Inhibitors; Serotonin; Sumatriptan; Triazoles

1. Recently, a new generation of monoamine oxidase (MAO) inhibitors has been developed which selectively and reversibly inhibit MAO-A activity. 2. One of these compounds, called brofaromine, has been administered in subjects suffering from endogenous depression, revealing antidepressive efficacy in a majority of them without inducing serious adverse events. 3. The results obtained so far suggest that brofaromine might be effective in endogenous depressed patients who failed to respond to tricyclic antidepressants.

Topics: Antidepressive Agents; Depressive Disorder; Humans; Monoamine Oxidase Inhibitors; Piperidines

Monoamine oxidase (MAO) inhibitors (MAOIs) provide effective alternative therapy for those patients with major depression who do not respond to tricyclic antidepressants or such related compounds as the selective serotonin reuptake inhibitors. This article reviews studies on the efficacy of both the classical MAOIs and the new, selective monoamine oxidase-A (MAO-A) inhibitor brofaromine in patients with resistant major depression. Brofaromine appears to be as effective as the older MAOIs in these patients, but is better tolerated and safer to use. Brofaromine was also found to be better tolerated than lithium when added to treatment with the tetracyclic antidepressant maprotiline. More studies on the benefits of the new MAO-A inhibitors in resistant depression are indicated, not only with brofaromine but also with moclobemide, which to date has not been studied in this indication. Studies to determine their place in the overall treatment strategy of major depression are also needed.

Topics: Antidepressive Agents; Depressive Disorder; Drug Resistance; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines

The authors' goals were to examine the effects of somatic treatment and placebo in patients with and without endogenous/melancholic depression.. Before entry into one of four trials of antidepressant drugs versus placebo, 231 patients were assessed as to whether they met Research Diagnostic Criteria for definite endogenous depression and/or DSM-III criteria for major depressive episode with melancholia. These patients were prospectively assessed for subsequent response to antidepressant treatment or placebo. Previous studies of the effect of endogenous/melancholic depression on treatment response were also reviewed.. Of the 76 patients with DSM-III melancholia given active medication, 41 (54%) had a complete or partial response, but only 10 (23%) of the 44 patients with melancholia given placebo had a complete or partial response. Of the 76 depressed patients without melancholia given active medication, 46 (61%) had a complete or partial response, and 15 (43%) of the 35 depressed patients without melancholia given placebo had a complete or partial response. Moderately depressed patients with DSM-III melancholia had a significantly better response to active medication than did severely depressed patients with melancholia and showed the greatest difference between response to active medication and response to placebo. The results of the review of previous studies of the effect of endogenous/melancholic depression on treatment response were mixed.. Depressed patients with melancholia were not particularly different from depressed patients without melancholia in their responses to antidepressant medication but did differ from patients without melancholia in their responses to active medication versus placebo, particularly if their depression was moderate and not severe. This suggests that patients with DSM-III melancholia may be unresponsive to nonsomatic treatments.

Topics: Antidepressive Agents; Depressive Disorder; Double-Blind Method; Fluoxetine; Humans; Imipramine; Oximes; Paroxetine; Piperidines; Placebos; Prospective Studies; Psychiatric Status Rating Scales; Treatment Outcome

The pharmacokinetic properties of the newer specific serotonin (5-HT) reuptake inhibitors are reviewed. Fluoxetine, paroxetine, sertraline, and fluvoxamine show kinetic characteristics similar to those of the older tricyclic antidepressants. They are well absorbed orally but exhibit an extensive first-pass extraction in the liver. They are widely distributed in body tissues and highly bound to plasma proteins. The clearance of these drugs by the body is accomplished almost entirely by hepatic metabolism. Fluoxetine and sertraline both produce a pharmacologically active metabolite, although insufficient data are available to evaluate the clinical significance of desmethylsertraline. With the exception of fluoxetine, which has an elimination half-life of 2 to 3 days, the other drugs have half-lives of about 1 day. Available data indicate that paroxetine and fluvoxamine achieve steady state within 4 to 14 days of chronic dosing, whereas for fluoxetine, and particularly norfluoxetine, steady state is not reached for weeks. The pharmacokinetics of these drugs are characterized by marked intersubject variability. Only preliminary data are available on steady-state plasma concentrations achieved during treatment and correlations to therapeutic or adverse effects.

Topics: 1-Naphthylamine; Depressive Disorder; Fluoxetine; Fluvoxamine; Humans; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Serotonin Antagonists; Sertraline

The dose regimen for paroxetine in the treatment of depression has been well established through a number of individual dosing studies and analyses from the worldwide clinical data base. The starting dose, which is also the minimal effective dose, is 20 mg/day. For most patients, 20 mg/day will also be the optimal dose. For patients who do not show an adequate therapeutic response within 1 to 3 weeks of initiating therapy, the dose of paroxetine should be increased in 10-mg increments no more often than at weekly intervals to a maximum of 50 mg/day. Medication should be given as a single daily dose, usually in the morning. The therapeutic dose range in the elderly is 20 mg to 40 mg of paroxetine.

Topics: Administration, Oral; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Multicenter Studies as Topic; Paroxetine; Piperidines

Paroxetine is a novel phenylpiperidine compound that acts as a selective serotonin reuptake inhibitor (SSRI). It is a more selective and potent SSRI than fluoxetine, sertraline, or fluvoxamine. Its pharmacokinetics are well suited to clinical use. Its half-life is approximately 24 hours, and it has no active metabolites. As with other SSRIs, there are few clinically significant drug interactions with paroxetine. Clinical studies consistently show that paroxetine alleviates moderate or severe depression and associated anxiety. It begins to act at least as rapidly as the tricyclic antidepressants. Animal data and limited human experience suggest relative safety in overdose and no evidence of teratogenicity. As with other SSRIs, the most common side effect of paroxetine is nausea, which is usually well tolerated. The nausea rarely leads to drug discontinuation or even dosage reduction. Little weight loss or weight gain occurs with paroxetine at doses used to treat depression, and the drug has no effect on the seizure threshold. Unlike other SSRIs, paroxetine has a relatively low incidence of anxiety and agitation. There is no evidence that paroxetine increases suicidal ideation. This supplement will contribute several important new papers to the literature on paroxetine.

Topics: Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Humans; Nausea; Paroxetine; Piperidines; Serotonin Antagonists

Side effects remain one of the most important clinical issues in antidepressant therapy. Patients may not be able to take appropriate treatment or may not tolerate their medication in adequate doses or for an adequate length of time to manage their depressive illness. This article reviews the extensive safety data from 6705 patients treated with paroxetine. These data indicate that paroxetine has no significant cardiovascular effects, few significant drug interactions, and no clinically significant effects on the ECG or EEG. Furthermore, paroxetine is relatively safe in overdose and has very little anticholinergic activity. Psychomotor performance is not impaired by paroxetine and there is no evidence of any zimelidine-like hypersensitivity reactions or increase in suicidal ideation. As with other selective serotonin reuptake inhibitors (SSRIs), the most common side effect is gastrointestinal upset, especially nausea. This is usually very well tolerated and rarely leads to drug discontinuation. As with other SSRIs, monoamine oxidase inhibitors should not be prescribed concurrently or soon after discontinuing paroxetine because of the risk of a lethal interaction. Paroxetine may be less likely than currently available SSRIs to cause agitation. In general, paroxetine has a very favorable side effect profile and should be an important alternative in the medical treatment of depressive illness.

Topics: Adult; Aged; Antidepressive Agents; Bipolar Disorder; Cardiovascular System; Clinical Trials as Topic; Depressive Disorder; Drug Interactions; Electrocardiography; Female; Humans; Male; Middle Aged; Neurocognitive Disorders; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Placebos; Psychomotor Performance; Sleep

Paroxetine is a highly potent and selective inhibitor of serotonin reuptake, being more potent in vitro than fluoxetine, fluvoxamine, and sertraline. In contrast to the tricyclic antidepressants, paroxetine has little affinity for catecholaminergic or histaminergic systems. Paroxetine is well absorbed from the gastrointestinal tract and undergoes first-pass metabolism that is partially saturable. Unlike the metabolites of fluoxetine and sertraline, the metabolites of paroxetine are pharmacologically inactive in vivo. Steady-state paroxetine plasma concentrations are generally achieved within 4 to 14 days of commencing therapy and remain stable thereafter. The pharmacokinetics of paroxetine are also consistent with once-daily dosing. This pharmacologic and pharmacokinetic profile, taken together with extensive clinical data, indicates that paroxetine is a valuable addition to the physician's armamentarium for the treatment of depression.

Topics: 1-Naphthylamine; Depressive Disorder; Fluoxetine; Fluvoxamine; Humans; In Vitro Techniques; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Serotonin Antagonists; Sertraline

The authors briefly review studies of the efficacy of potent serotonin reuptake inhibitors (SRIs) (e.g., clomipramine, fluvoxamine) in obsessive compulsive disorder (OCD) and compare the use of antidepressants in the treatment of depression and OCD. They propose an algorithm for those patients with OCD who fail to respond to an adequate trial with a potent SRI and discuss the promise and limitations of adding tryptophan, fenfluramine, lithium, buspirone, or a neuroleptic to ongoing SRI therapy. Other biological approaches (e.g., ECT, psychosurgery) are considered in terms of their narrowly defined roles in the treatment of patients with SRI-resistant OCD.

Topics: 1-Naphthylamine; Antidepressive Agents; Clomipramine; Depressive Disorder; Fluoxetine; Fluvoxamine; Humans; Neurotransmitter Uptake Inhibitors; Obsessive-Compulsive Disorder; Paroxetine; Piperidines; Serotonin; Sertraline

Paroxetine is a potent and selective inhibitor of the neuronal reuptake of serotonin, thereby facilitating serotoninergic transmission; this action appears to account for the antidepressant activity observed with this drug. A mean terminal elimination half-life of approximately 24 hours permits once daily administration. Results of short term clinical trials have shown paroxetine to be significantly superior to placebo, and comparable to amitriptyline, clomipramine, imipramine, dothiepin and mianserin in relieving symptoms associated with major depressive disorders. Paroxetine has shown some preliminary promise in the treatment of depressive illness resistant to tricyclic antidepressant therapy but further studies are required before any conclusions can be drawn. Paroxetine in therapeutic doses has been very well tolerated, and the favourable tolerability profile of this agent appears to be its primary advantage over traditional antidepressant agents. Paroxetine causes minimal anticholinergic-type adverse effects, and unlike tricyclic antidepressants, it does not precipitate cardiovascular effects or provoke cardiac conduction disturbances. Nausea has been the most frequently reported adverse event during short term use of paroxetine, but it is generally mild and transient and subsides with continued use. With longer term use headache, sweating and constipation were the most frequently reported side effects but the incidence rate was not significantly different from that noted for comparator antidepressants. Furthermore, the frequency of withdrawal due to adverse effects is less with paroxetine than with tricyclic antidepressant agents. Overall, available data appear to indicate that while the efficacy of paroxetine is similar to that of traditional antidepressant drugs, the newer agent possesses much improved tolerability. In addition, the wide therapeutic index of paroxetine may be beneficial when treating patients with an increased risk of suicide. Thus, paroxetine clearly looks to become a valuable addition to the range of drugs currently available to treat depressive illness. Future research may help to further define the relative place of this newer agent in antidepressant therapy and determine how its overall therapeutic efficacy compares with that of other related antidepressant agents such as fluoxetine.

Topics: Amitriptyline; Animals; Antidepressive Agents; Clomipramine; Depressive Disorder; Drug Evaluation; Drug Tolerance; Humans; Imipramine; Paroxetine; Piperidines; Serotonin Antagonists

Antidepressant drugs undoubtedly reduce much of the morbidity and mortality associated with a variety of depressive disorders. Certain types of antidepressant drugs have been shown to exert a relative advantage in the reduction of suicidal thoughts, and it is interesting that recent reports have noted an association between the prescription of some antidepressants and the development of suicidal and aggressive thoughts and behaviour. An analysis of the data from double-blind controlled trials of fluvoxamine, fluoxetine and paroxetine indicates that 5-HT uptake inhibitors exercise some protective effects on the emergence of suicidal thoughts, whereas the data from the studies with maprotiline show an increase in suicidal thoughts compared with placebo.

Topics: Antidepressive Agents; Depressive Disorder; Dose-Response Relationship, Drug; Fluoxetine; Fluvoxamine; Humans; Mianserin; Paroxetine; Piperidines; Serotonin Antagonists; Suicide; Suicide Prevention

The clinical pharmacology, adverse event profiles, and clinical efficacy of several serotonin reuptake inhibitors are summarized and compared with those of the classic tricyclic antidepressants. Serotonin reuptake inhibitors discussed are sertraline, zimelidine, fluoxetine, fluvoxamine, and paroxetine. While they do not differ from tricyclics in efficacy or onset of action, the serotonin reuptake inhibitors clearly have a different side effect potential. Unlike tricyclics, serotonin reuptake inhibitors provide effective antidepressant activity without sedating, anticholinergic, or cardiotoxic reactions. In comparison, tricyclics lower the seizure threshold, have anticholinergic and hypotensive effects, affect cardiac conduction, are dangerous in overdose, and may cause weight gain. The primary adverse events associated with serotonin reuptake inhibitors involve the gastrointestinal system, although side effects may be less frequent at lower dosage levels. It is important to choose antidepressant therapy on the basis of a patient's ability to tolerate the specific adverse reactions that may occur with a given agent. Although serotonin reuptake inhibitors have not replaced the tricyclics, they are a useful addition to the variety of drugs currently used for the treatment of depression.

Topics: 1-Naphthylamine; Antidepressive Agents, Tricyclic; Depressive Disorder; Fluoxetine; Humans; Paroxetine; Piperidines; Serotonin Antagonists; Sertraline; Zimeldine

The efficacy of 5-HT uptake inhibitors, including paroxetine, as antidepressants is compared with that of the reference tricyclic antidepressants. It is suggested that some of the older tricyclic antidepressants might not have been released for general clinical use if tested by today's rigorous standards. Placebo-controlled, multicentre studies indicate that 5-HT uptake inhibitors are both effective as antidepressants and well tolerated by depressed patients. They also appear to have a role in the treatment of depression when associated with personality disorders, in the treatment of obsessive-compulsive disorder and bulimia, and in resistant depression. Moreover, the evidence for efficacy in the prophylaxis of depression is better established for 5-HT uptake inhibitors than for reference antidepressants.

Topics: Antidepressive Agents; Depressive Disorder; Humans; Long-Term Care; Paroxetine; Piperidines; Serotonin Antagonists

Paroxetine is well absorbed from the gastrointestinal tract, and appears to undergo first-pass metabolism which is partially saturable. Consistent with its lipophilic amine character, paroxetine is extensively distributed into tissues. Its plasma protein binding at therapeutically relevant concentrations is about 95%. Paroxetine is eliminated by metabolism involving oxidation, methylation, and conjugation. All of these factors lead to wide interindividual variation in the pharmacokinetics of paroxetine. Renal clearance of the compound is negligible. The major metabolites of paroxetine are conjugates which do not compromise its selectivity nor contribute to the clinical response. Ascending single-dose studies reveal that the pharmacokinetics of paroxetine are non-linear to a limited extent in most subjects and to a marked degree in only a few. Also, steady-state pharmacokinetic parameters are not predictable from single-dose data. In many subjects, daily administration of 20-50 mg of paroxetine leads to little or no disproportionality in plasma levels with dose, although in a few subjects this phenomenon is evident. Steady-state plasma concentrations are generally achieved within 7 to 14 days. The terminal half-life is about one day, although there is a wide intersubject variability (e.g. with 30 mg, a range of 7-65 hours was observed in a group of 28 healthy young subjects). In elderly subjects there is wide interindividual variation in steady-state pharmacokinetic parameters, with statistically significantly higher plasma concentrations and slower elimination than in younger subjects, although there is a large degree of overlap in the ranges of corresponding parameters. In severe renal impairment higher plasma levels of paroxetine are achieved than in healthy individuals after single dose. In moderate hepatic impairment the pharmacokinetics after single doses are similar to those of normal subjects. Paroxetine is not a general inducer or inhibitor of hepatic oxidation processes, and has little or no effect on the pharmacokinetics of other drugs examined. Its metabolism and pharmacokinetics are to some degree affected by the induction or inhibition of drug metabolizing enzyme(s). From a pharmacokinetic standpoint, drug interactions involving paroxetine are considered unlikely to be a frequent occurrence. Data available have failed to reveal any correlation between plasma concentrations of paroxetine and its clinical effects (either efficacy or adverse eve

Topics: Antidepressive Agents; Depressive Disorder; Drug Interactions; Humans; Metabolic Clearance Rate; Paroxetine; Piperidines; Serotonin Antagonists

During the last years the MAO-inhibitors reached a progressive importance in clinical practice. It was attempted to solve problems of tolerability by a new generation of MAO-inhibitors. Brofaromine is a MAO-inhibitor of the second generation, a selective, reversible and short acting MAO-A-inhibitor, promising that the dangerous "cheese effect" will occur only under extreme conditions. The clinical trials performed hitherto, among other double-blind test versus tranylcypromine and imipramine, demonstrate a good antidepressive efficacy and a good tolerability.

Topics: Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Humans; Piperidines

Depression has been associated with a disturbance in serotonin function as reflected in platelet uptake of the transmitter as well as in CSF levels of its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA). CSF 5-HIAA levels are subnormal in approximately 30% of melancholia patients. Early studies suggested that patients with a disturbed serotonin metabolism were less responsive to treatment with uptake inhibitors with a preferential action on noradrenaline neurons. Such findings encouraged the search for compounds with a selective effect on serotonin neurons. Although some classical antidepressants are potent inhibitors of serotonin uptake, they are not selective, since their metabolites, which appear to have antidepressant effects, inhibit noradrenaline uptake. The consistent findings of an increased risk for suicide in patients with low CSF 5-HIAA underlines the importance of exploring drugs that act on serotonin transmission. The biochemical effects of some serotonin uptake inhibitors and their clinical and research potential in depression are reviewed.

Topics: 5-Hydroxytryptophan; Alanine; Citalopram; Depressive Disorder; Fluoxetine; Fluvoxamine; Humans; Imipramine; Oximes; Paroxetine; Piperidines; Propylamines; Serotonin; Serotonin Antagonists; Trazodone; Zimeldine

Treatment strategies for patients with depression and cognitive impairment (DEP-CI), who are at high risk to develop a clinical diagnosis of dementia, are not established. This issue is addressed in the donepezil treatment of cognitive impairment and depression (DOTCODE) pilot clinical trial. The DOTCODE study is the first long-term treatment trial that assesses differences in conversion to dementia and cognitive change in DEP-CI patients using a study design of open antidepressant medication plus add-on randomized, double-blind, placebo-controlled treatment with the acetylcholinesterase inhibitor donepezil. In Phase 1, DEP-CI patients receive optimized antidepressant treatment for 16 weeks. In Phase 2, antidepressant treatment is continued with the addition of randomized, double-blind treatment with donepezil or placebo. The total study duration for each patient is 78 weeks (18 months). Eighty DEP-CI outpatients (age 55 to 95 years) are recruited: 40 at New York State Psychiatric Institute/Columbia University and 40 at Duke University Medical Center. The primary outcome is conversion to a clinical diagnosis of dementia. The secondary outcomes are cognitive change scores in Selective Reminding Test (SRT) total recall and the modified Alzheimer's Disease Assessment Scale (ADAS-cog). Other key assessments include the 24-item Hamilton Depression Rating Scale and antidepressant response; Clinical Global Impression (CGI) for depression, cognition, and global status; neuropsychological test battery for diagnosis; informant report of functional abilities (Pfeffer FAQ); and Treatment Emergent Symptom Scale (TESS) for somatic side effects. Apolipoprotein E ε4 status, odor identification deficits, and MRI entorhinal/hippocampal cortex atrophy at baseline are evaluated as neurobiological moderators of donepezil treatment effects.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Antidepressive Agents; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Depressive Disorder; Donepezil; Double-Blind Method; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Piperidines; Research Design

To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship.. The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD.. Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score > or =10; n = 208) and nondepressed (BDI <10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants.. Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antioxidants; Brain; Cholinesterase Inhibitors; Cognition Disorders; Depressive Disorder; Disease Progression; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Placebos; Severity of Illness Index; Time Factors; Tocopherols; Treatment Outcome

To assess combined antidepressant and cognitive enhancer treatment in elderly patients presenting with depression plus cognitive impairment.. Twenty-three elderly (>50 years old) depressed, cognitively impaired (DEP-CI) patients participated in a pilot study. We evaluated whether, after 8 weeks of open antidepressant treatment, donepezil HCl (Aricept) would afford added cognitive benefit compared to placebo in a randomized 12-week trial. A subsample continued in an 8-month extension phase of open treatment with donepezil. Neuropsychological testing (NPT) was performed and antidepressant response monitored at baseline and the 8, 20, and 52-week time points.. At 8-weeks, the antidepressant response rate was 61% (14/23). Improvement in SRT immediate recall (SRT-IR; e.g. episodic verbal memory) was observed in responders compared to non-responders. During the 12-week, placebo-controlled, donepezil add-on trial, patients on donepezil showed further improvement in SRT-IR versus patients on placebo. In the open extension phase, patients who continued open donepezil treatment (n = 6) maintained improvement in memory and tended to show an advantage over patients who never received donepezil and were evaluated at the 52-week time point (n = 6). There were no observed significant donepezil effects on non-memory cognitive domains.. These preliminary findings suggest that addition of a cholinesterase inhibitor (AChEI) following antidepressant medication treatment in elderly Dep-CI patients may improve cognition, and support the need for a confirmatory, larger randomized placebo-controlled trial.

Topics: Aged; Antidepressive Agents; Cholinesterase Inhibitors; Cognition Disorders; Depressive Disorder; Donepezil; Epidemiologic Methods; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Sertraline; Treatment Outcome

Cognitive impairment and negative signs are common in patients with schizophrenia. Up to 35% of elderly patients with schizophrenia fulfill the diagnostic criteria of dementia. Donepezil inhibits cholinesterase, thus enhancing cholinergic neurotransmission. We tested the efficacy of donepezil in elderly patients with chronic schizophrenia and severe cognitive impairment.. Following baseline assessment, patients were randomly assigned to receive either donepezil or placebo. The dose was 5 mg daily for the first week and 10 mg for an additional 11 weeks. The procedure was repeated using the crossover compound. The Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI) and Alzheimer Disease Assessment Scale - Cognitive subscale (ADAS-Cog) were used to assess the severity of symptoms, cognitive status and intervention effects.. Twenty subjects were enrolled (15 females, five males), mean age 70.2 years (SD 6.5) and mean duration of disease 38.5 years (SD 9.3). A modest treatment effect was found for both placebo and donepezil treatment periods. No crossover effect was found. No statistical differences were demonstrated between the two treatment groups (CGI p = 0.37, PANSS p = 0.71, ADAS-Cog p = 0.86). Two patients died during the study period due to unrelated causes and one patient discontinued participation due to increased agitation.. Donepezil does not seem to improve negative signs and cognitive impairment in elderly patients with chronic schizophrenia.

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Chronic Disease; Cognition Disorders; Comorbidity; Cross-Over Studies; Dementia; Depressive Disorder; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Remifentanil is a short acting opioid frequently used to supplement general anesthesia for brief procedures. Narcotic agents are known for their ability to blunt autonomic responses to stimuli such as laryngoscopy and intubation and do not alter seizure threshold. We hypothesized that the combination of remifentanil and methohexital for induction would produce favorable suppression of sympathetic response during electroconvulsive therapy (ECT). With Institutional Review Board approval and informed consent, patients were enrolled in a prospective, randomized, double-blind, crossover study of methohexital alone versus remifentanil with an adjuvant of low-dose methohexital. One hundred ten ECT treatments were evaluated and subjects were treated in an alternating fashion with one of two induction protocols: Methohexital alone in an 80-100 mg IV bolus or remifentanil 500 mcg IV bolus combined with methohexital 40 mg IV. Bilateral ECT was performed in standard fashion and systolic blood pressure and heart rate were recorded throughout the procedure. No significant differences were found in baseline hemodynamic values between the two groups. Heart rate was significantly lower in the remifentanil group versus methohexital group at one minute post-induction and just prior to ECT stimulus. Pre-ECT systolic blood pressure was not significantly different between the two groups. Heart rate remained lower in the remifentanil group at all measured timepoints during the treatment and continuously for five minutes after the seizure. Systolic blood pressure was significantly lower at one minute following the end of seizure and five minutes after end of seizure. Remifentanil's short duration of action, favorable side effect profile, potential proconvulsant activity and ability to suppress hemodynamic response make it a potential novel drug for ECT induction.

Topics: Anesthesia; Anesthetics, Intravenous; Blood Pressure; Cross-Over Studies; Depressive Disorder; Drug Therapy, Combination; Electroconvulsive Therapy; Heart Rate; Humans; Methohexital; Middle Aged; Piperidines; Prospective Studies; Remifentanil; Sympathetic Nervous System

Donepezil is an acetylcholinesterase inhibitor marketed for treatment of memory loss and behavioral deterioration associated with the acetylcholine deficit of Alzheimer's disease. We investigated the utility and tolerability of donepezil in nongeriatric affective illness for treatment of psychotropic-induced memory loss, dry mouth, and constipation.. Nondemented outpatients with stabilized DSM-IV affective illness took 5 mg/day of donepezil for 3 weeks and then increased to 10 mg/day in open trials. Self-rating scales of target symptoms were completed by patients before and 3 to 4 weeks after starting each dose condition. Patients who chose to continue donepezil therapy returned for clinical monitoring every 4 to 8 weeks.. Eleven women and 11 men (mean +/- SD age = 45.4+/-8.5 years) completed donepezil trials. Nineteen patients with memory loss rated improvement while taking 5 mg/day of donepezil (p<.001); subsequently, 6 rated further improvement with 10 mg/day (p = .057). Donepezil, 5 mg/day, also reduced ratings of dry mouth (N = 16; p<.001) and constipation (N = 11; p<.05). Side effects included insomnia, nausea, vomiting, and diarrhea; surprisingly, 2 bipolar patients became manic within hours of starting donepezil. Sixteen patients (72%) continued donepezil for an average of 7 months. Consideration of family histories suggested that donepezil response in affective illness may be an early indicator of vulnerability to dementia of the Alzheimer's type.. (1) Donepezil can reduce memory loss, dry mouth, and constipation in nongeriatric affective patients, but may trigger mania; and (2) long-term follow-up will reveal the predictive value for dementia of donepezil's memory restoration in nongeriatric subjects.

Topics: Adult; Ambulatory Care; Cholinesterase Inhibitors; Constipation; Depressive Disorder; Diarrhea; Dizziness; Donepezil; Drug Administration Schedule; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Piperidines; Psychotropic Drugs; Sleep Initiation and Maintenance Disorders; Xerostomia

Brofaromine is a selective and reversible inhibitor of monoamine oxidase A. The efficacy and safety of this compound as compared with tricyclic antidepressants, classical monoamine oxidase inhibitors and placebo has been demonstrated in several clinical trials. The present 6-week, double-blind, randomized trial compared brofaromine with imipramine in in-patients with major depression. Brofaromine was as effective as imipramine in the treatment of major depression, but exhibited a different side-effect profile, in particular lacking the anticholinergic and certain cardiovascular side-effects of the tricyclic imipramine, but more likely to induce sleep disturbances. In this study, in-patients were examined, since the majority of controlled clinical trials on depressed patients conducted so far have focused on the evaluation of out-patients. If one assumes that a different degree of severity of depression exists between these two patient groups, then the results of those trials conducted on out-patients cannot readily be transferred to in-patients.

Topics: Adolescent; Adult; Aged; Antidepressive Agents, Tricyclic; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hospitalization; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Sleep Wake Disorders

The timing of clinical drug effects in depression can be estimated by a variety of methodological approaches, which might account for the heterogeneity of findings. We compared the patients' own ratings of the onset of antidepressant effect with onset estimations that were based on the intraindividual courses of depression as measured by the Hamilton Depression Rating Scale and a self-rating scale, the von Zerssen Adjective Mood Scale. The data of two control-group studies on brofaromine vs. imipramine were reanalyzed, the first, comprising 224 non-elderly and the second 195 elderly patients. In both studies the patients rated a significantly earlier onset of activity (means: days 12 and 16) than any other method. The means of the scale-based ratings varied between days 20 and 31 and showed a marked dependence on the response criteria selected: strict response criteria produced later onset estimations than less strict ones. Whereas the patient's own ratings indicated a significantly later onset of activity in the elderly patients, none of the scale-based measures supported this difference. The discussion focuses on the importance of methodological aspects.

Topics: Adult; Aged; Antidepressive Agents; Antidepressive Agents, Tricyclic; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales

Low doses of cisapride (5-10 mg twice daily) produced relatively rapid relief from nausea elicited by venlafaxine in six patients with treatment-refractory recurrent major depression. This further suggests that the nausea associated with serotonergic reuptake inhibition may be a result of 5-hydroxytryptamine (5-HT3) agonist action. No adverse cardiac experiences were encountered in spite of the potential interaction of cisapride with selective serotonin reuptake inhibitors at the cytochrome P4503A4 enzyme system.

Topics: Adult; Antidepressive Agents, Second-Generation; Cisapride; Cyclohexanols; Depressive Disorder; Drug Resistance; Female; Humans; Male; Middle Aged; Nausea; Piperidines; Psychiatric Status Rating Scales; Serotonin Antagonists; Venlafaxine Hydrochloride

Risperidone is a new-generation atypical antipsychotic agent with potent dopaminergic and serotonergic antagonist activity. Compared with traditional dopamine-blocking neuroleptics, risperidone is more effective in treating negative symptoms of schizophrenia and may be less likely to cause extrapyramidal symptoms or tardive dyskinesia. Although risperidone is marketed for the treatment of schizophrenia, its novel psychopharmacologic effects and potentially mild side effect profile suggest the possibility of other therapeutic applications. An open prospective study was undertaken to determine whether risperidone might diminish psychosis, severe agitation, or rapid cycling in patients having acute and chronic primary affective illnesses (bipolar and major depressive disorder) and to document response characteristics and side effects. Additionally, a small number of patients with refractory obsessive-compulsive disorder (OCD) without comorbid tic or delusional disorders were given open trials of risperidone added to their medication.. Outpatients who fulfilled DSM-IV criteria for bipolar I, bipolar II, or major depressive disorder and suffered from psychosis or agitation associated with their illness (N = 20) and those who had treatment-refractory DSM-IV OCD (N = 5) were started on open trials of risperidone at daily doses of 1 to 1.5 mg. Doses were adjusted upwards to a maximum of 6 mg depending on clinical response.. Seventeen (85%) of 20 patients (13 bipolar, 4 major depressive disorder) showed complete or partial improvement after treatment with risperidone doses ranging from 1 to 6 mg/day (mean = 3.5 mg). Beneficial effects included decreases in agitation, psychosis, sleep disturbance, and rapid cycling. Four patients (20%) discontinued risperidone because of intolerable side effects. Five patients with refractory OCD also showed significant symptomatic improvement after the addition of risperidone.. The findings suggest that (1) risperidone may be useful in the acute/p.r.n. and chronic treatment of psychosis, agitation, and cycling accompanying affective illness, and (2) risperidone may be useful in augmenting pharmacologic response in OCD.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Bipolar Disorder; Depressive Disorder; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoxazoles; Male; Middle Aged; Obsessive-Compulsive Disorder; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Risperidone; Treatment Outcome

There is a rather limited database of controlled clinical trials on the comparative effects of antidepressants in elderly and non-elderly depressed patients. A common finding is reduced efficacy and an increased incidence of side effects. To further examine the question of efficacy and safety of antidepressant drugs in elderly versus non-elderly patients, the differential effects of a new selective type A monoamine oxidase inhibitor brofaromine, and the classical tricyclic imipramine were investigated using the data of two recently published trials. We found no major difference between non-elderly and elderly depressed patients as concerns efficacy, total incidence of adverse findings or safety parameters such as laboratory values and heart rate. These results are discussed in the light of some methodological questions and previous reports.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Antidepressive Agents, Tricyclic; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales

Most findings of antidepressant treatment prediction have not been replicated, and this applies to biological predictors as well as sociodemographic and early course predictors. One exception might be early psychopathological improvement. To reevaluate this question, we examined the results of two large-scale controlled clinical trials comparing the selective and reversible inhibitor of monoamine oxidase type A (MAO-A) brofaromine with the standard tricyclic compound imipramine. One trial was carried out in a normal-aged patient group; the other, in elderly patients. Above all, we were interested in determining whether early treatment course would prove predictive of later outcome. The main finding was that the initial antidepressant effect (measured after 1 and 2 weeks) predicted longer term outcome. Although this association was not as strong in the elderly patient group, its predictive value did possess a certain clinical relevance.

Topics: Adult; Affect; Aged; Antidepressive Agents, Tricyclic; Depressive Disorder; Double-Blind Method; Female; Geriatric Assessment; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Piperidines; Prognosis; Treatment Outcome

In a 6-week double-blind study, 220 patients with major depression (mostly outpatients) were randomly assigned to receive a fixed dose of brofaromine 150 mg daily (n = 111) or placebo (n = 109) after a 1-week single-blind placebo washout. Except for the HAM-D sleep items, brofaromine was superior to placebo on measures of depression as determined by the four methods of assessing drug efficacy: (1) psychiatric symptom rating (HAM-D 17-item less the three sleep items); (2) self-rating scale (Beck Depression Inventory); (3) Clinical Global Assessment of Efficacy; and (4) drop-out rate due to lack of efficacy. Most commonly reported adverse events with brofaromine were: headache, nausea, dizziness and sleep disturbance. Brofaromine was found to be an effective antidepressant, superior to placebo with a good tolerability profile.

Topics: Adolescent; Adult; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Piperidines

In a controlled, double-blind, comparative four-week trial on reactive or neurotic major depressed inpatients, the efficacy and safety of the new selective and reversible inhibitor of monoamine oxidase type A, brofaromine, was evaluated in three dose steps (50 mg/day [N = 13], 100 mg/day [N = 12], and 150 mg/day [N = 11]) versus 20 mg tranylcypromine/day (N = 11). In the four groups a pronounced reduction of the depressive symptomatology (measured by the Hamilton Depression Scale, the Zung Self-Rating Scale of Depression, and by a global evaluation of efficacy) was found, but it was not possible to show any differential effect. The safety parameters in all groups were comparable. The results of the trial are compared with other trials of monoamine oxidase inhibitors in this patient group and the possible reasons for the lack of a clear dose-response relationship are discussed.

Topics: Adolescent; Adult; Aged; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales; Tranylcypromine

The predictive value of eight domains or sets of variables including sociodemographic aspects, premorbid history, symptomatology, personality, social and diagnostic data are evaluated in depressed outpatients with a Hamilton Rating Scale for Depression (HRSD) score of at least 14. Patients were treated using a three-phase sequential treatment strategy. Of the 119 patients, 88 completed the trial. The HRSD-score at the end of phases I, II or III was used as an outcome measure. Patients with an initially high HRSD-score and an obsessive-compulsive personality had a greater chance of recovery, while patients with somatization and a passive-aggressive personality had less of a chance of recovery. Variables involving psychiatric history, premorbid history or symptomatology of the depression, were not significantly related to outcome. The endogenous/non-endogenous distinction was not a predictor of response.

Topics: Adult; Antidepressive Agents; Cross-Over Studies; Depressive Disorder; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Lithium; Male; Maprotiline; Middle Aged; Monoamine Oxidase Inhibitors; Personality Assessment; Personality Inventory; Piperidines; Treatment Outcome

In a controlled clinical inpatient trial (n = 93) comparing the efficacy and safety of brofaromine versus tranylcypromine for 6 weeks in treatment-resistant major depressed patients, the two drugs were found to be of comparable afficacy and tolerability. The response rate (a 50% reduction) on the Hamilton Scale for Depression (HAMD) in both groups was about 73%. The most common side effects in the brofaromine group were sleep disorders, hypotension, tremor and dryness of mouth; and in the tranylcypromine group sleep disorders, fatigue, hypotension, tremor and vertigo. Methodological and practical clinical implications of the results are discussed.

Topics: Adult; Aged; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Piperidines; Tranylcypromine

Depressed outpatients (n = 51) resistant to treatment with maprotiline were treated in a blind, randomized, single-centre study, for 6 weeks with either the reversible and selective monoamine oxidase A-inhibitor (MAO-A-I), brofaromine or lithium addition to maprotiline. The Hamilton Rating Scale for Depression was scored by an independent rater before and after the 6 week treatment period. No significant differences in efficacy were found between the two treatment regimes. In the patients who completed the trial, brofaromine was well tolerated with the exception of insomnia. Anticholinergic effects as well as thyroid dysfunctions (17 out of 20) were more frequent in the maprotiline/lithium group.

Topics: Adolescent; Adult; Aged; Depressive Disorder; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lithium; Male; Maprotiline; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Piperidines; Prospective Studies; Recurrence

In an 8-week controlled double-blind clinical trial with a total of 189 elderly patients brofaromine showed comparable efficacy to imipramine (Hamilton Depression Scale, von Zerssen self-rating scale, global evaluation). The numbers of adverse events were the same in both groups, but the spectrum differed distinctly. In the global evaluation of tolerability, there was an advantage for brofaromine. Mean daily doses were 85 mg/day in the brofaromine group and 87 mg/day in the imipramine group. Long-term efficacy and tolerability also proved to be good in the open follow-up of the patients treated with brofaromine.

Topics: Aged; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Follow-Up Studies; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales

Brofaromine is a new, reversible, and selective type-A monoamine oxidase inhibitor (MAOI) that also has serotonin reuptake inhibitory properties. Its dual pharmacologic effects offer promise in the treatment of a wide spectrum of depressed patients while producing less severe anticholinergic side effects in comparison with standard drugs. A multicenter, double-blind, placebo-controlled study including 220 patients was undertaken to evaluate the efficacy and safety of brofaromine in major depression. This study of a fixed-dose design and 6 weeks' duration found that brofaromine was significantly better than placebo on the Overall Evaluation of Efficacy, Beck self-rating scale, HAM-D Bech subscale, HAM-D total 14 items (minus the three sleep items), HAM-D depressed mood item and retardation factor, and worse than placebo on the insomnia items of HAM-D. Significantly more patients on placebo than on brofaromine did not complete the trial due to lack of efficacy. In comparative controlled studies (n = 899), brofaromine was found to be at least as efficacious as tricyclic antidepressants (imipramine) and standard MAOIs (tranylcypromine and phenelzine). Reductions of at least 50% in the HAM-D total score were seen in 58-66% of patients treated with either brofaromine or imipramine (n = 609). Brofaromine also was found to be of comparable efficacy to tranylcypromine in two clinical trials (n = 132), one of which included patients considered to have a treatment-resistant depression (n = 39). In another double-blind study that compared brofaromine (150 mg/day) to phenelzine (45 mg/day) (n = 158), there was no difference between brofaromine and phenelzine.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Canada; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Phenelzine; Piperidines; Psychiatric Status Rating Scales; Tranylcypromine

Topics: Adult; Aged; Depressive Disorder; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Regression Analysis; Sleep Wake Disorders

In a double-blind study the selective monoamine oxidase-A inhibitor brofaromine was compared with the classical MAOI tranylcypromine in 39 patients with major depression resistant to treatment with tricyclic antidepressants. Concerning efficacy no significant differences were found. Ten out of 22 patients responded to brofaromine and 5 out of 17 patients to tranylcypromine. Adverse effects favoured brofaromine. Although orthostatic hypotension occurred in both groups, severe decrease in blood pressure and dizziness occurred significantly more with tranylcypromine. Both MAOIs caused a decrease in stage 4 and REM sleep and an increase in REM latency. In most patients receiving tranylcypromine REM sleep was completely abolished.

Topics: Adult; Depressive Disorder; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypotension, Orthostatic; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales; Sleep, REM; Tranylcypromine

The selective, reversible monoamine oxidase (MAO) A inhibitor brofaromine inhibits serotonin (5-HT) uptake in animal models in vitro and in vivo. We investigated whether such an effect can be demonstrated at clinical doses in humans by treating three groups of six volunteers with either placebo, 15 mg phenelzine three times a day, or 75 mg brofaromine twice a day in a 2-week experiment. As an indirect, although relevant parameter, binding of 3H-paroxetine to the 5-HT uptake sites on blood platelets was assessed. Moreover, whole-blood 5-HT as a measure of platelet 5-HT, and serum homovanillic acid (HVA) to tentatively estimate MAO inhibition, were determined. Brofaromine reduced 3H-paroxetine binding to platelets compared with placebo by 20%-25% throughout the treatment period, significance being reached on the last treatment day. In contrast, phenelzine tended to increase 3H-paroxetine binding. Both drugs increased whole-blood 5-HT to approximately 140%-150%. Brofaromine moderately and on some days significantly decreased serum HVA, whereas phenelzine only tended to do so. Our results suggest that brofaromine at the clinically used dosage of 150 mg/day does indeed inhibit 5-HT uptake, as evidenced by measurements of 3H-paroxetine binding to platelets.

Topics: Adult; Depressive Disorder; Homovanillic Acid; Humans; Male; Monoamine Oxidase Inhibitors; Paroxetine; Piperidines; Placebos; Selective Serotonin Reuptake Inhibitors

The items of the HAM-D(17-item version) were analyzed by a nonmetric (ordinal) multi-dimensional scaling procedure (Smallest Space Analysis, SSA-I) and the structure of the test items characterized within the framework of Guttman's facet theory. Two systematic components (facets) were discerned: 'centrality' and 'aspect'. Properties of the facets as well as their relations were assessed and examined empirically by analyzing the inter-relations among different items. The spatial configurations obtained by the scaling procedure were found only partially to fit the expectations derived from the facet-theory model. The facet 'centrality' was found to have a strong overriding influence over the 'aspect' facet. The results suggest the value of a new combination and selection of items reflecting different facets of depression consistently over time.

Topics: Adolescent; Adult; Aged; Amitriptyline; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Factor Analysis, Statistical; Female; Humans; Male; Middle Aged; Models, Statistical; Paroxetine; Personality Inventory; Piperidines; Prospective Studies; Psychometrics; Serotonin Antagonists

This study evaluated the relationship of sociotropic and autonomous personality traits with response to pharmacotherapy for 217 depressed outpatients using the Sociotropy-Autonomy Scale. Sociotropy was related to nonendogenous depression, whereas autonomy was related to endogenous depression. Subjects who had high autonomous-low sociotropic traits showed greater response to antidepressants (and greater drug-placebo differences) than those who had high sociotropic-low autonomous traits (who showed no drug-placebo differences). Hierarchical multiple regression analysis showed that the sociotropy-autonomy, but not the endogenous-nonendogenous, distinction was a predictor of drug treatment response. The combination of endogeneity and autonomy predicted response to placebo. If replicated, these findings may enable better matching of patient traits to various treatment modalities for depression.

Topics: Adult; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Fluoxetine; Humans; Imipramine; Individuality; Internal-External Control; Interpersonal Relations; Male; Oximes; Paroxetine; Piperidines; Serotonin Antagonists

To assess the effects of treatment on symptoms of anxiety and agitation associated with depression, a data base of 2963 paroxetine treated patients was compared with 554 who received placebo and 1151 on active control. Paroxetine and active control both reduced baseline psychic anxiety more effectively than placebo. Both pharmacological treatments were effective in treating somatic anxiety with active control demonstrating an earlier onset of activity. Neither paroxetine nor active control induced new anxiety symptoms. Paroxetine was superior to placebo in the treatment of agitation at Weeks 4 and 6 and to active control at Week 4 only. Both paroxetine and active control were more protective against emergent (new) agitation than placebo. There was no difference between the three groups in the incidence of spontaneously reported adverse events indicative of anxiety.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Anxiety; Depressive Disorder; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Psychiatric Status Rating Scales

The authors' goals were to examine the effects of somatic treatment and placebo in patients with and without endogenous/melancholic depression.. Before entry into one of four trials of antidepressant drugs versus placebo, 231 patients were assessed as to whether they met Research Diagnostic Criteria for definite endogenous depression and/or DSM-III criteria for major depressive episode with melancholia. These patients were prospectively assessed for subsequent response to antidepressant treatment or placebo. Previous studies of the effect of endogenous/melancholic depression on treatment response were also reviewed.. Of the 76 patients with DSM-III melancholia given active medication, 41 (54%) had a complete or partial response, but only 10 (23%) of the 44 patients with melancholia given placebo had a complete or partial response. Of the 76 depressed patients without melancholia given active medication, 46 (61%) had a complete or partial response, and 15 (43%) of the 35 depressed patients without melancholia given placebo had a complete or partial response. Moderately depressed patients with DSM-III melancholia had a significantly better response to active medication than did severely depressed patients with melancholia and showed the greatest difference between response to active medication and response to placebo. The results of the review of previous studies of the effect of endogenous/melancholic depression on treatment response were mixed.. Depressed patients with melancholia were not particularly different from depressed patients without melancholia in their responses to antidepressant medication but did differ from patients without melancholia in their responses to active medication versus placebo, particularly if their depression was moderate and not severe. This suggests that patients with DSM-III melancholia may be unresponsive to nonsomatic treatments.

Topics: Antidepressive Agents; Depressive Disorder; Double-Blind Method; Fluoxetine; Humans; Imipramine; Oximes; Paroxetine; Piperidines; Placebos; Prospective Studies; Psychiatric Status Rating Scales; Treatment Outcome

In an 8-week controlled double-blind clinical trial with a total of 216 patients Brofaromine was found to be superior to Imipramine with regard to efficacy (Hamilton Depression Scale, von Zerssen self-rating scale, global evaluation) and tolerability (adverse experiences, global evaluation). Mean daily dosages were 93.1 mg/day in the Brofaromine group and 92 mg/day in the Imipramine Group. No tyramine reduced diet had to be observed. Long-term efficacy and tolerability also proved to be good in an open follow-up in the Brofaromine group.

Topics: Adult; Depressive Disorder; Double-Blind Method; Female; Follow-Up Studies; Humans; Imipramine; Long-Term Care; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Piperidines

Topics: Depressive Disorder; Humans; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales; Single-Blind Method

Paroxetine is an investigational antidepressant that acts through selective inhibition of serotonin reuptake at the synapse. In this study, 81 outpatients with major depression according to DSM-III criteria were treated with either paroxetine or placebo in a 6-week, randomized, double-blind study. Paroxetine was significantly superior to placebo on all major efficacy variables, including depression as well as anxiety, cognitive disturbance, insomnia, psychomotor retardation, and sleep disturbance. Significant differences in favor of paroxetine were apparent by Week 2. Paroxetine was also well tolerated. The results support the efficacy and safety of paroxetine as a treatment for patients with major depression.

Topics: Ambulatory Care; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Drugs, Investigational; Humans; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Placebos; Psychiatric Status Rating Scales

Paroxetine, a phenylpiperidine derivative, is an antidepressant that selectively inhibits serotonin reuptake. In this study 111 outpatients with major depression diagnosed by DSM-III criteria were treated with either paroxetine or placebo in a 6-week, randomized, double-blind study. Paroxetine was significantly superior to placebo on six of the seven major efficacy variables. Significant differences in favor of paroxetine were apparent by Week 2. Paroxetine was also well tolerated. These results support the efficacy and safety of paroxetine as a treatment for patients with major depression.

Topics: Adult; Ambulatory Care; Antidepressive Agents; Depressive Disorder; Female; Humans; Male; Middle Aged; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Placebos; Psychiatric Status Rating Scales

Considerable research shows that serotonin dysfunction is implicated in major depression. Paroxetine is an investigational antidepressant that appears to act by selectively blocking neuronal serotonin uptake. Seventy-two outpatients with moderate-to-severe major depression entered this 6-week, double-blind comparison of paroxetine and placebo. The results showed clear and significant superiority of paroxetine on all of the major outcome variables. These included physician-rated measures such as the Hamilton Rating Scale for Depression and its four factor scores, the Clinical Global Impressions scale, the Montgomery and Asberg Depression Rating Scale, and the Raskin Depression Scale. Results on these agreed well with patient-rated measures like the Hopkins Symptom Checklist and Patient Global Evaluation Scale. Paroxetine was also very well tolerated. Nausea and constipation occurred significantly more often with paroxetine, but only 9% of paroxetine patients dropped out of the study due either in whole or in part to an adverse effect. This compares to 8% of the placebo patients who were discontinued for the same reason. This study suggests that paroxetine is a safe and effective medication for the treatment of major depression.

Topics: Adult; Ambulatory Care; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Placebos; Psychiatric Status Rating Scales

Paroxetine is a phenylpiperidine compound that selectively inhibits neuronal serotonin uptake in man. In this study, the efficacy of paroxetine was compared with that of placebo in the treatment of 66 outpatients with the diagnosis of moderate-to-severe major depression. The research was a 6-week, prospective, double-blind design after a 1-week placebo baseline phase. Paroxetine was associated with a consistent pattern of greater improvement on the primary efficacy scales, but the differences were not statistically significant. Paroxetine did produce significantly greater improvement than placebo for patients whose illness had lasted more than 1 year, and there was a significant reduction in suicidal ideation. Significantly fewer dropouts were due to lack of efficacy in those patients treated with paroxetine compared with those in the placebo group. Paroxetine was well tolerated. There was no difference between paroxetine and placebo in the rate of adverse effects or in the number of patients who dropped out because of adverse effects.

Topics: Adult; Ambulatory Care; Antidepressive Agents; Depressive Disorder; Female; Humans; Male; Neurotransmitter Uptake Inhibitors; Paroxetine; Patient Dropouts; Piperidines; Placebos; Psychiatric Status Rating Scales; Suicide; Time Factors

Paroxetine is a novel antidepressant that selectively inhibits neuronal reuptake of serotonin. Results are reported from a 6-week, double-blind trial of paroxetine, imipramine, and placebo in 120 outpatients with DSM-III major depression. Paroxetine was significantly superior to placebo on almost all measures. This included the main outcome variable, the Hamilton Rating Scale for Depression (HAM-D), and its factor scores, anxiety-somatization, cognitive disturbance, psychomotor retardation, and sleep disturbance. There were no significant differences between paroxetine and imipramine on the same scales. Imipramine-treated patients were significantly more likely than those taking placebo to report one or more adverse effects, which were predominantly anticholinergic in nature. There was no significant difference in the number of paroxetine and placebo patients who reported one or more adverse effects. The results of this and similar studies indicate that paroxetine is an effective treatment in major depression and has a favorable side effect profile.

Topics: Adult; Ambulatory Care; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Neurotransmitter Uptake Inhibitors; Paroxetine; Patient Dropouts; Piperidines; Placebos; Psychiatric Status Rating Scales

Paroxetine is a selective serotonin reuptake inhibitor with significant antidepressant properties. This was a 6-week placebo- and imipramine-controlled study of 120 outpatients with major depression. Paroxetine was statistically significantly superior to placebo on almost all outcome measures. This was apparent as early as 1 week. Paroxetine was also significantly superior to imipramine on the Hamilton Rating Scale for Depression total score. Paroxetine was generally better tolerated than imipramine. These results strongly support paroxetine's effectiveness in the treatment of major depression and suggest that paroxetine will be a valuable addition to the options in treating depressive illness.

Topics: Adolescent; Adult; Ambulatory Care; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Neurotransmitter Uptake Inhibitors; Paroxetine; Patient Dropouts; Piperidines; Placebos; Psychiatric Status Rating Scales

Results from a single-center, 6-week, double-blind, randomized prospective study of paroxetine, a selective serotonin reuptake inhibitor; imipramine; and placebo are reported. One hundred twenty outpatients with a moderate-to-severe DSM-III diagnosis of major depression were randomly assigned to one of the three treatments following a 4- to 10-day single-blind placebo washout period. Significant differences favoring paroxetine over placebo were present at endpoint on most major efficacy measures. Paroxetine was also well tolerated; 5 (15%) paroxetine and 5 (14%) placebo patients dropped out of the study due to adverse effects. Imipramine, however, was comparatively poorly tolerated. Forty-five percent of imipramine-treated patients (N = 17) dropped out of the study due to adverse effects. None of the efficacy measures showed a significant difference between imipramine and placebo. This finding was probably due to the high number of imipramine patients who discontinued before they could improve. These results support the efficacy of paroxetine in the treatment of major depression and underline its favorable side effect profile compared with tricyclic antidepressants.

Topics: Adult; Ambulatory Care; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Neurotransmitter Uptake Inhibitors; Paroxetine; Patient Dropouts; Piperidines; Placebos; Prospective Studies; Psychiatric Status Rating Scales

Paroxetine is a selective serotonin reuptake inhibitor which is being developed as an antidepressant. Previous studies suggest it is effective in the treatment of depression and has a low incidence of side effects. The authors report on a 6-week, randomized, prospective trial of paroxetine, imipramine, and placebo in 120 outpatients with major depression. The results showed that paroxetine was significantly superior to placebo in relieving depression. There were no significant differences in antidepressant efficacy between paroxetine and imipramine. However, paroxetine was also significantly superior to placebo on several measures of anxiety. Imipramine either was not superior on these measures or took longer to show a significant difference. Paroxetine lacked the typical anticholinergic side effects that accompanied imipramine therapy. The results show that paroxetine is an effective antidepressant that may have value especially when depression is accompanied by significant anxiety.

Topics: Adult; Antidepressive Agents; Anxiety Disorders; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Placebos; Prospective Studies

Depressive illness among the elderly is an important public health concern. However, treatment of the elderly may be complicated by age-related changes in physiology, general medical status, and susceptibility to side effects. There is therefore a need for improved treatment modalities for depressed elderly patients. Paroxetine is an antidepressant that acts through selective inhibition of serotonin reuptake. It lacks the anticholinergic and cardiovascular side effects of most first- and second-generation antidepressants. The authors present the combined data from two similarly designed comparisons of paroxetine and doxepin in outpatients over 60 years of age with major depression. The results show that paroxetine was an effective as doxepin in alleviating depression as measured on the Hamilton Rating Scale for Depression (HAM-D) total score, the Montgomery and Asberg Depression Rating Scale (MADRS), and the Hopkins Symptom Checklist (SCL) depression factor score. Paroxetine was significantly superior to doxepin on the Clinical Global Impressions (CGI) scale for severity of illness, the HAM-D retardation factor, and the HAM-D depressed mood item. Doxepin produced significantly more anticholinergic effects, sedation, and confusion. Paroxetine was associated with more reports of nausea and headache. These results suggest that paroxetine may be a valuable tool for the treatment of major depression in the elderly.

Topics: Age Factors; Aged; Ambulatory Care; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Doxepin; Female; Humans; Male; Middle Aged; Neurotransmitter Uptake Inhibitors; Paroxetine; Patient Dropouts; Piperidines; Psychiatric Status Rating Scales

In a double-blind clinical study, antidepressant plasma levels, parameters of platelet serotonin (5-HT) transport (Km, Vmax and basal platelet 5-HT content) and therapeutic response were measured in depressive patients treated with either paroxetine (30 mg/day) or amitriptyline (150 mg/day) for 6 weeks. No correlation could be found between paroxetine plasma levels and therapeutic outcome after 2, 4 and 6 weeks of treatment. In contrast to the amitriptyline group, a marked increase in Km from baseline to week 2 was determined in paroxetine-treated patients, with Km increase being correlated with paroxetine plasma levels at week 2. However, no significant relationship could be found between 5-HT transport parameters and any of the outcome measures in either treatment group.

Topics: Adult; Amitriptyline; Antidepressive Agents; Blood Platelets; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Nortriptyline; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Receptors, Serotonin; Serotonin; Serotonin Antagonists

Topics: Adult; Aged; Ambulatory Care; Depressive Disorder; Humans; Imipramine; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Placebos; Recurrence; Serotonin; Serotonin Antagonists

In a 12-week double-blind study with 36 patients with major depressive episode (DSM-III), paroxetine (Seroxat, Aropax) showed significantly quicker onset of efficacy on the Melancholia Scale, and better tolerance than imipramine. Plasma concentration analyses showed no clear concentration-efficacy correlation in either treatment group. During long-term treatment paroxetine seemed to be superior to imipramine in preventing relapse; both treatments were well tolerated. A significant correlation between baseline plasma tryptophan: large neutral amino acids ratio and final Hamilton Rating Scale for Depression (HRSD) score and a trend towards an inverse correlation between this ratio and percentage reduction in HRSD score were seen in the paroxetine group but not in the imipramine group. In line with previous studies, these results support the hypothesis that paroxetine is an effective and well tolerated antidepressant.

Topics: Amino Acids; Antidepressive Agents; Bipolar Disorder; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Imipramine; Male; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Serotonin Antagonists

To compare the safety and antidepressant efficacy of paroxetine, imipramine, and placebo, data from six centres using the same protocol were pooled. A double-blind parallel-group design was used, with therapy lasting six weeks. From week 2 onwards, both the 240 paroxetine-treated and the 237 imipramine-treated patients were significantly different from the 240 placebo-treated patients, but no different from each other. Side-effects with paroxetine were less likely to lead to drop-out than with imipramine. Paroxetine had a possible earlier antidepressant effect than imipramine, and a possible earlier beneficial effect on anxiety symptoms associated with depression.

Topics: Adult; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Middle Aged; Paroxetine; Personality Tests; Piperidines; Serotonin Antagonists

Thirty patients suffering from dysthymic disorder participated in a 6-week double-blind trial comparing ritanserin 10 mg and placebo. After a single-blind placebo wash-out period of one week, the test medication was administered during 5 weeks on a double-blind basis. Twenty-three patients completed the study. At the end of the trial, ritanserin was significantly superior to placebo in its effect as manifested on the 19-item Hamilton Rating Scale for Depression, the Hamilton Rating Scale for Anxiety and the State Trait Anxiety Inventory X-1 and X-2. At the end of the study, the therapeutic effect was rated marked or moderate in 75% of the ritanserin-treated patients, but only in 18% of the controls. These data are consistent with the hypothesis of serotonin abnormalities in dysthymic disorder and suggest a therapeutic role of 5-HT2 antagonists. Ritanserin treatment was very well tolerated; no serious adverse experiences were reported.

Topics: Adult; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Personality Inventory; Piperidines; Placebos; Psychiatric Status Rating Scales; Receptors, Serotonin; Ritanserin; Serotonin Antagonists

N = 53 inpatients with major depressive disorder have been treated with the reversible, selective MAO-A-inhibitors moclobemide (double-blind versus maprotiline) and brofaromine (open study), respectively. Clinically, significant improvement of depression and an activating profile of action could be observed, typical side effects were sleep disturbances, agitation and weight loss. The neurobiochemical data showed an increase of noradrenaline plasma concentrations under treatment with moclobemide. Visual reaction times improved with antidepressant treatment. MAO-A inhibitors proved to be effective antidepressants in the treatment of hospitalized patients with predominantly endogenous depressions.

Topics: Benzamides; Catecholamines; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Moclobemide; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales

The thyrotropin-releasing hormone (TRH) test was performed in 100 depressed patients, including 73 patients with a major depressive episode (MDE) according to DSM-III. Thirty-one patients subsequently received an antidepressant with a predominant serotoninergic action (indalpine or citalopram), and 27 patients received a noradrenergic antidepressant (maprotiline). The diagnostic value of the TRH test was not conclusive for any of the subgroups of depressed patients: MDE, MDE with melancholia or MDE in bipolar patients. Similarly, the value of the TRH test in the choice of antidepressant treatment according to the monoaminergic action was not convincing. These results are discussed in the light of the data of the international literature.

Topics: Adult; Aged; Bipolar Disorder; Citalopram; Depressive Disorder; Female; Humans; Male; Maprotiline; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Recurrence; Serotonin Antagonists; Thyrotropin; Thyrotropin-Releasing Hormone

The pretreatment plasma ratio of tryptophan (Trp) to other large neutral amino acids (LNAA), thought to reflect brain serotonin formation, was determined in 44 inpatients with major depression, who were subsequently treated double-blind on a fixed-dose schedule for 4 weeks with the selective serotonin uptake inhibitor paroxetine (n = 27) or clomipramine (n = 17). The study took place at four clinical centers. Endogenous and non-endogenous depressives were comparable with respect to the ratio Trp/LNAA and clinical improvement and were therefore analyzed together. The clomipramine group showed a significant inverse correlation between ratio Trp/LNAA and improvement, and patients with a ratio Trp/LNAA below the mean showed a trend towards greater improvement than patients with a higher ratio but with comparable serum drug levels. The improvement in the paroxetine group was significantly inversely correlated with the Trp concentration but not with the ratio Trp/LNAA. The findings accord with previous trials of various antidepressant treatments, in which about 25% of the variance in therapeutic response associates with pretreatment plasma amino acid profiles.

Topics: Adult; Aged; Amino Acids; Clinical Trials as Topic; Clomipramine; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Serotonin Antagonists; Tryptophan

Antidepressant effects and unintended effects of paroxetine (30 mg/day) and clomipramine (150 mg/day) were compared in a double-blind, randomized, inpatient, fixed-dose, plasma-level-controlled study. Patients with a DSM-III diagnosis of major depressive disorder participated. After 1 week of single-blind placebo treatment 120 patients fulfilled the criterion of a Hamilton (17-item) score of greater than or equal to 18 and were started on active treatment for 6 weeks. Drop-outs on paroxetine (n = 12) were largely due to lack of effect, and on clomipramine (n = 19) due to lack of effect (n = 7), adverse reactions or severe side effects (n = 10) and development of mania (n = 2). According to the protocol, non-responders (Hamilton total greater than or equal to 16) after 4 weeks active treatment were terminated, and this occurred to 23 patients on paroxetine and four patients on clomipramine. Categorical response measures and group averages of rating scores showed a significantly better therapeutic effect of clomipramine from the second week of treatment on. These results are very similar to our earlier results with another selective serotonin reuptake inhibitor (citalopram), but generally at variance with the literature on this class of antidepressants, which, however, mostly deals with outpatient studies.

Topics: Adult; Antidepressive Agents; Clomipramine; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Multicenter Studies as Topic; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Serotonin Antagonists

The objective of this study was to compare the safety and efficacy of paroxetine with imipramine and placebo in depressed outpatients. Following a 4- to 14-day placebo washout, patients were randomized into treatment groups and received study compound for up to 42 days. At Day 42, paroxetine was significantly more effective than placebo (p less than .05) in several observer- and patient-rated scales: the Retardation and Anxiety/Somatization factors of the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Raskin Depression Scale, the Covi Anxiety Scale, the Clinical Global Impressions (CGI) Improvement Scale, the Symptom Checklist-56 (SCL-56) Total, and the Patient's Global Evaluation (PGE). There were no significant differences between paroxetine and imipramine. Significantly more imipramine (75%) than paroxetine (35%) or placebo (23%) patients reported anticholinergic side effects, including blurred vision (5%, 0%, and 0%, respectively), constipation (35%, 8%, and 15%, respectively), and dry mouth (63%, 25%, and 15%, respectively). The data from this study indicated that paroxetine is a safe, well-tolerated, effective treatment for major depressive disorder.

Topics: Adult; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Paroxetine; Piperidines; Psychiatric Status Rating Scales

A placebo-controlled, randomized, double-blind study was carried out in outpatients suffering from major unipolar depressive disorder to assess the efficacy and tolerability of paroxetine in the treatment of depression. The study lasted for six weeks. After a placebo washout period of 4 to 14 days patients took 20mg of paroxetine or matched placebo as a morning dose for one week; thereafter the dose of paroxetine could be titrated between 10 and 50mg/day. Patients were evaluated at baseline, weekly during the first four weeks of the study, and at the end of six weeks; patients who entered a six-week extension phase were evaluated at 9 and 12 weeks. Evaluations were carried out using HAMD (including ECDEU factors), MADRS, HSCL, Covi anxiety and Raskin depression scales, CGI, and a seven-point rating of global improvement. Adverse events and laboratory values were also recorded at each assessment. One hundred and eleven patients entered the study, and efficacy data were available for 102 of these (49 on paroxetine and 53 on placebo). Efficacy measurements demonstrated significantly greater clinical improvement with paroxetine than placebo after two weeks of treatment, and this became even more marked after six weeks. Patients who continued treatment for a further six weeks maintained their clinical improvement. When adverse events were examined, statistically significant differences between paroxetine and placebo were seen only for sweating, diarrhoea, nausea, and somnolence. No significant changes were seen in any of the laboratory parameters measured. If these results are confirmed in future studies, paroxetine will represent an important addition to the treatments available for depression.

Topics: Adult; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Serotonin Antagonists

Topics: Antidepressive Agents; Arousal; Blood Pressure; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Electrocardiography; Electroencephalography; Heart Rate; Humans; Paroxetine; Piperidines; Serotonin Antagonists

Paroxetine is a selective serotonin uptake inhibitor, which is being investigated as an antidepressant. In this double-blind, six-week study 120 outpatients with DSM-III major depression were randomly assigned to treatment with paroxetine, imipramine, or placebo. Results showed a statistically significant superiority of paroxetine over placebo on almost all outcome measures. Paroxetine was significantly superior to imipramine on the HAMD total score and was generally better tolerated than imipramine. The results support paroxetine's effectiveness in the treatment of major depression and suggest that further studies with this compound are warranted.

Topics: Antidepressive Agents; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Imipramine; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Serotonin Antagonists

Topics: Aged; Antidepressive Agents; Clomipramine; Depressive Disorder; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Serotonin Antagonists

Topics: Aged; Antidepressive Agents; Clomipramine; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Serotonin Antagonists

Topics: Adolescent; Adult; Aged; Amitriptyline; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Drug Evaluation; Female; Hospitals, Psychiatric; Humans; Male; Meta-Analysis as Topic; Middle Aged; Paroxetine; Piperidines; Randomized Controlled Trials as Topic; Serotonin Antagonists

Topics: Antidepressive Agents; Bipolar Disorder; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Humans; Mianserin; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Serotonin Antagonists

Topics: Adult; Amitriptyline; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Serotonin Antagonists

Topics: Adult; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Serotonin Antagonists

Topics: Amitriptyline; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Humans; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Serotonin Antagonists

Topics: Adult; Amitriptyline; Antidepressive Agents; Blood Platelets; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Paroxetine; Piperidines; Randomized Controlled Trials as Topic; Serotonin; Serotonin Antagonists

To evaluate the pharmacokinetic properties, efficacy, and tolerability of paroxetine in elderly depressed patients, a clinical study was set up--initially at Aalborg Psychiatric Hospital in Denmark, and subsequently at the University Hospital in Linköping, Sweden. A total of 21 patients with a median age of 72 years were included in the study. After a single dose of 20 or 30 mg of paroxetine followed by two drug-free days, treatment continued with 20 or 30 mg daily for seven weeks. The majority of patients showed a continuous reduction in their HAMD scores, starting in the second week of treatment. Paroxetine was well tolerated at the doses given, and side-effects were mostly mild and transient. Steady-state, pre-dose plasma levels of paroxetine showed considerable variability, and the median steady-state concentration was higher in elderly patients compared with data from a previous study in young volunteers. Elimination half-lives also showed variability between these elderly patients, but tended to be longer after cessation of multiple dosing than after a single dose. They also tended to be longer than in the young volunteers. The results of this study do not advocate reduced doses of paroxetine in the elderly, but further studies are warranted.

Topics: Aged; Aged, 80 and over; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Serotonin Antagonists

Topics: Adult; Aged; Antidepressive Agents; Depressive Disorder; Dose-Response Relationship, Drug; Humans; Middle Aged; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Serotonin Antagonists

Topics: Aged; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Paroxetine; Piperidines; Serotonin Antagonists

Topics: Antidepressive Agents; Depressive Disorder; Double-Blind Method; Humans; Imipramine; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic

Topics: Antidepressive Agents; Depressive Disorder; Double-Blind Method; Humans; Imipramine; Paroxetine; Piperidines; Randomized Controlled Trials as Topic

We evaluated the dexamethasone suppression test (DST) as a predictor of response to drugs and placebo in 105 patients, in a large double-blind placebo-controlled out-patient trial to determine the efficacy of paroxetine HCl, a selective serotonin reuptake inhibitor, compared with that of imipramine HCl and placebo. The presence of a positive or negative DST did not predict response to either paroxetine or imipramine. However, a positive DST predicted a poorer response to placebo: only 3 out of 18 patients who showed DST non-suppression responded to placebo, as opposed to 11 out of 21 who exhibited DST suppression (P less than 0.05). A positive DST was associated with a 61% response to drugs and a 16% response to placebo. This finding suggests that the presence of a positive DST implies the need for active somatic treatment.

Topics: Adult; Ambulatory Care; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Dexamethasone; Double-Blind Method; Female; Humans; Hydrocortisone; Imipramine; Male; Middle Aged; Paroxetine; Piperidines; Placebos; Predictive Value of Tests; Psychiatric Status Rating Scales

Brofaromine (CGP 11 305 A), a new reversible and selective MAO-A inhibitor, was studied in two multicentre, (Trial A and Trial B) double-blind, dose-finding trials in a total of 124 depressed in-patients. Doses of 25, 50 and 75 mg bid were compared, to determine which was the most effective. The duration of the trials was four weeks. The comparative drugs were nomifensine (100 mg/day) and tranylcypromine (20 mg/day). The majority of patients in the Trial A was classified as "endogenous" depression. Diagnosis of depression was based on DSM-III or ICD-9 criteria. Conversely, most of the patients in Trial B were "non-endogenous" depressives. In "endogenous" depression, a statistically significant linear dose-response relationship was found in all the efficacy variables assessed. The most effective dose was 150 mg/day. This dose gave a mean drop of 25.3 +/- 11.9 (S.D.) points in the total Hamilton Depression Rating Scale (HAMD) scores and provided successful treatment in 83% of the patients treated, success being defined as a drop of at least 50% in the initial HAMD score at the end of the trial period. In "non-endogenous" depression, no statistical difference was found between the four treatment groups in any of the efficacy variables assessed. Response rate in all brofaromine groups averaged 59% (tranylcypromine group 60%). Tolerability was good in 90% or more of the brofaromine patients in both trials, regardless of the dose administered. The side effects reported most frequently were sleep disturbances, nausea, and headaches.

Topics: Adult; Aged; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Nomifensine; Piperidines; Psychiatric Status Rating Scales; Random Allocation; Tranylcypromine

During the last years the MAO-inhibitors reached a progressive importance in clinical practice. It was attempted to solve problems of tolerability by a new generation of MAO-inhibitors. Brofaromine is a MAO-inhibitor of the second generation, a selective, reversible and short acting MAO-A-inhibitor, promising that the dangerous "cheese effect" will occur only under extreme conditions. The clinical trials performed hitherto, among other double-blind test versus tranylcypromine and imipramine, demonstrate a good antidepressive efficacy and a good tolerability.

Topics: Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Humans; Piperidines

Paroxetine is a new antidepressant drug. It is a potent and selective 5-HT re-uptake inhibitor with only weak anticholinergic properties and less effect on the cardiovascular system than the classical tricyclics. In this double-blind multicenter study the antidepressant effect of paroxetine was compared with mianserin in 70 patients with unipolar or bipolar depression. Each drug was administered for 6 weeks after a 1 week run-in period at a daily dosage of 30 mg for paroxetine or 60 mg for mianserin. The 21-item Hamilton Depression Rating Scale (HAM-D) and the physician's global assessment were used to assess efficacy. Both treatment groups showed statistically significant improvement of the HAM-D at Weeks 1 (base-line values: paroxetine mean 28.5; mianserin mean 30.8) through to Week 6 (paroxetine mean 11.5; mianserin mean 17.8) (P less than 0.06). The endpoint differences between treatments however were not statistically different (P = 0.11). The Cleary and Guy factor analysis showed a significant difference (P less than 0.03) at Weeks 2 and 4 for cognitive disturbance and at Weeks 4 and 6 for retardation in favour of paroxetine compared with mianserin. Both drugs were well tolerated with nausea and headache in four patients and somnolence in six patients being reported as the most common side-effect for paroxetine and mianserin respectively.

Topics: Adult; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Mianserin; Paroxetine; Piperidines; Psychiatric Status Rating Scales

Fifty-two patients with depressive illness characterized by four symptoms (periodical course, psychomotor retardation, diurnal variation, unrealistic self-depreciation) and a score of at least 18 on the Hamilton Depression Scale 1-17 (HDS) were allocated to a double-blind randomized study with femoxetine and imipramine. Patients were diagnosed according to RDC and further classified according to the Newcastle-II index. During the six weeks of treatment, efficacy was evaluated by means of HDS and a global evaluation. Side-effect symptoms were recorded on a check-list by questioning. After six weeks of treatment with femoxetine or imipramine (recommended daily standard dosages are 600 mg femoxetine and 150 mg imipramine (b.i.d.); in the present study, dosages were flexible and could be adjusted according to effect/side-effects) evaluation of efficacy based on HDS, a six-item subscale, groups of HDS items as well as single items showed no statistically significant differences between the treatment groups except with regard to the factor for sleep disturbances in the HDS, where greatest reduction was seen in the femoxetine group. No statistically significant differences regarding side-effect profile were seen. However, in the imipramine group, higher frequencies of such moderate to severe symptoms as dry mouth, constipation and urination difficulties were observed (the greatest difference was seen for dry mouth, p 0.1, while p-values for the remaining two symptoms were greater than 0.1). Moreover, based on the patients' own opinion on side-effects, femoxetine seemed to be better tolerated. One patient took an overdosage of approx. 26 g femoxetine; half of the intake was removed by gastric emptying at the hospital.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Half-Life; Humans; Imipramine; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Random Allocation; Time Factors

Ritanserin, a selective and potent serotonin-2 antagonist, is effective in the treatment of a variety of syndromes related to anxiety and depression, including dysthymic disorder. In animals and healthy volunteers, ritanserin specifically increases slow-wave sleep and the hypothesis arises that this effect on sleep may contribute to its therapeutic properties. Therefore, we studied the effects of ritanserin on sleep in a group of dysthymic patients (DSM-III). Polygraphic recording as well as subjective evaluations of the quality of sleep were performed before and at the end of a 4-week period of double-blind medication with either ritanserin (10 mg o.d. in the morning) or placebo. At baseline, patients showed at fragmented and superficial sleep, with low amounts of slow wave sleep. Ritanserin significantly increased Slow Wave Sleep and changed the frequency and distribution of some stage transitions during the night. No other sleep parameters were modified by ritanserin treatment.

Topics: Adult; Depressive Disorder; Female; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Ritanserin; Serotonin Antagonists; Sleep Stages; Sleep Wake Disorders; Sleep, REM

Topics: Clinical Trials as Topic; Depressive Disorder; Humans; Piperidines; Ritanserin; Schizophrenia; Serotonin Antagonists; Sleep

Ifoxetine (CGP 15 210 G) is a novel and unusual drug. It specifically and selectively blocks the 5-HT reuptake in the brain without affecting the 5-HT uptake processes in the periphery (blood platelets). In the first, open and explorative trials its tolerability and effectiveness were studied in 33 patients suffering from endogenous (n = 25) or other types of depressive disorders. In daily doses of 50 to maximally 300 mg mental condition considerably improved in 17 patients. As assessed by HAMD 7 patients out of 17 became asymptomatic (HAMD Score less than 10) whereas 10 other patients markedly improved (decrease in HAMD by greater than or equal to 50%) in the course of 3 to 4 weeks of treatment. Eleven patients improved only slightly, in 3 patients no particular change in condition could be observed and 2 patients deteriorated. This deterioration was due to psychotic decompensation after the second week of the treatment (75-100 mg/d). Apart from this, ifoxetine was well tolerated particularly at doses of 50-150 mg/day, which also appeared to be the optimal therapeutic range of doses. There were no changes in cardiovascular function or laboratory values and almost no somatic or other complaints of major concern. These preliminary results indicate that ifoxetine has antidepressant properties with possibly an advantageous side-effect profile, in comparison to other 5-HT uptake inhibitors.

Topics: Adult; Aged; Clinical Trials as Topic; Depressive Disorder; Female; Humans; Male; Middle Aged; Piperidines; Serotonin Antagonists

After 1 mg DST, 25 major depressive patients (DSM-III) received at random either a specific inhibitor of noradrenaline reuptake (Maprotiline) or an inhibitor of serotonin reuptake (Indalpine or Citalopram). After at least 3 weeks of treatment, no difference was found in treatment response between suppressors and non suppressors. This study is unable to confirm the usefulness of the DST in selection of treatment according to its central activity on serotonin or noradrenaline-reuptake.

Topics: Adult; Aged; Anthracenes; Citalopram; Depressive Disorder; Dexamethasone; Female; Humans; Male; Maprotiline; Middle Aged; Piperidines; Propylamines

Patients with a depressive illness with 4 major symptoms of depression and a score of at least 17 on the Hamilton Depression Scale (1-17) (HDS) were allocated to a randomized double-blind group comparative study in general practice. After retrospective analysis, all 81 patients except one were characterized as suffering from a 'Definite Major Depressive Disorder', as defined by Spitzer et al. (1978). After 6 weeks of treatment with a daily dosage of 600 mg femoxetine or 150 mg amitriptyline, no statistically significant differences between the 2 treatment groups were observed, either when using the HDS or the clinical global assessment scale. Confidence limits of 95% for differences between therapeutic effect showed a non-significant tendency in favour of amitriptyline. During treatment, there were statistically significant differences in the reduction of HDS score between the 2 treatments in week 2. These differences were the result of amitriptyline's significantly greater effect on the 3 sleep items at week 2, as indicated by the results of single item analysis. Drop out rates due to side effects were between 14-15% in both treatment groups. Of the patients treated with femoxetine, 38% experienced no side effects, compared to 14% of patients treated with amitriptyline. Nausea was the side effect most commonly reported by patients treated with femoxetine, whereas a significantly greater frequency of anticholinergic side effects was recorded during treatment with amitriptyline (P less than 0.05). Unlike amitriptyline, femoxetine did not increase body weight. Treatment with the active drug was continued after the trial period in 14 and 18 patients in the femoxetine and amitriptyline groups respectively.

Topics: Adolescent; Adult; Aged; Amitriptyline; Antidepressive Agents; Body Weight; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Random Allocation; Serotonin

Paroxetine is a new antidepressant drug with potent serotonin (5HT) uptake inhibitory properties. In this double-blind comparative study, the antidepressant effect of paroxetine and amitriptyline has been compared in 44 patients with depressive illnesses of an endogenous nature. Each drug was given for 6 weeks. The 17-item Hamilton Depression Scale was used to measure the antidepressant effect. Reported events were assessed applying a 22-item check list. Non-parametric statistical analyses were applied in the evaluation of treatment outcome for the 30 patients who completed the study. The results showed no significant differences in overall antidepressant efficacy between paroxetine and amitriptyline and that paroxetine displayed significantly fewer instances of dry mouth and orthostatic dizziness than amitriptyline. No obvious relationship was demonstrated between the plasma levels of the drugs and their clinical effects.

Topics: Adult; Aged; Amitriptyline; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Random Allocation; Serotonin Antagonists

21 depressed patients of the Basle University Psychiatric Outpatient Clinic were treated in a double-blind study with paroxetine and amitriptyline. 11 of these patients did not continue the trial until the end of the 7th week. There was a significant difference in the number of dropouts between the two groups: 80% of the amitriptyline group did not continue until the end, while in the paroxetine group we found only 30% dropouts. The patients of both groups showed a gradual decrease of the median total scores on the Hamilton and the Montgomery and Asberg Depression Rating Scales. Although the number of patients who stayed in the trial for at least 4 weeks (8 with paroxetine, 6 with amitriptyline) is quite small, we see from the results of the clinical global impression that the members of the paroxetine group improved most of all in the somatic symptoms, while considering their moods we found no differences between the groups. Patients of both groups complained about side effects, most of all about dry mouth and tiredness. From the high rate of dropouts under amitriptyline we found that the side effects under this drug were more severe and therefore led to the dropouts.

Topics: Adolescent; Adult; Amitriptyline; Arrhythmias, Cardiac; Depressive Disorder; Double-Blind Method; Electroencephalography; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Psychiatric Status Rating Scales

Indalpine 150 mg per day and mianserin 60 mg per day were compared in a double-blind study of 65 depressed out-patients: 52 patients completed the 4-week trial. At the end of four weeks there was no significant difference in antidepressant effect between the two drugs; but in the first two weeks, improvement in the mianserin-treated group was significantly greater than that in the indalpine group. The mianserin-treated group reported more side-effects of sedation (eg. drowsiness, clumsiness, heaviness of limbs etc.) and one patient on indalpine developed a mild leucopenia.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Bipolar Disorder; Clinical Trials as Topic; Depressive Disorder; Dibenzazepines; Double-Blind Method; Humans; Leukopenia; Mianserin; Middle Aged; Piperidines

In this double-bind randomized study involving 35 depressed female inpatients, Indalpine proved significantly superior to placebo on all the criteria used: Hamilton scales for depression and anxiety, clinician's vectorial ratings. Its rapid onset of action was further confirmed by the rapid appearance of significance relative to placebo: as early as the third day of treatment, that is, during the optimum placebo effect period. The results are all more valuable if one considers the magnitude of the placebo effect obtained with daily infusions of isotonic sodium chloride-dextros solution, the possible adjunction of a benzodiazepine and the availability of placebo tablets as an adjunct to the infusions upon request. Acceptabilité was found to be good, especially at the cardiovascular and cholinergic levels.

Topics: Adult; Brief Psychiatric Rating Scale; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Kinetics; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Random Allocation

The antidepressant and biochemical effects of femoxetine, a selective serotonin uptake inhibitor, and desipramine, a selective nor-adrenaline uptake inhibitor, have been compared in a double-blind study in 42 outpatients with depressive illness. The patients were allocated at random to treatment with either 600 mg femoxetine or 150 mg desipramine daily for 6 weeks. The total depression score showed a significant decrease in both groups, indicating an overall improvement in depressive symptoms. The patients treated with femoxetine reported significantly less severe anticholinergic effects during the whole treatment period than the desipramine patients. Both drugs, decreased the level of 5-HIAA in CSF, whereas no consistent changes were found in the MHPG and HVA levels. The pretreatment level of the metabolites had no predictive value for the outcome of the treatment with either drug. No significant correlation was found between therapeutic effect and the plasma concentration of the active compounds.

Topics: Adult; Aged; Antidepressive Agents; Depressive Disorder; Desipramine; Double-Blind Method; Female; Glycols; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Phenylacetates; Piperidines

The new selective serotonin (5-HT)-uptake inhibitor femoxetine was compared with amitriptyline in a double-blind clinical trial comprising 77 depressed patients. The depressive symptoms were evaluated with the Hamilton rating scale, and a global clinical evaluation. Both drugs showed an antidepressive effect and no significant differences were found. Femoxetine induced a significantly lower frequency of dry mouth and blurred vision; this difference is presumably due to the weak anticholinergic effect of this substance. A small but significant weight loss was observed in the femoxetine group but not in the amitriptyline group.

Topics: Amitriptyline; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales

Clinical and experimental work indicates that cholinergic functions might play a role in modulating affectivity in man. In this acute double-blind study either the cholinolytic agent biperiden or placebo infusions were administered to six depressed females. The Janke and Debus self-rating questionnaire (EWL-K), the modified Hamilton depression scale (HAM-D), and the Montgomery and Asberg depression scale (MADRS) were used for documentation of psychopathological change. There was an acute antidepressant effect during infusion of the active drug in comparison to placebo as measured on the global MADRS and EWL-K, but not on the modified HAM-D. Single items such as depressed mood, work and interests (HAM-D), sadness, concentration difficulties, inability to feel (MADR-S), and depressiveness (EWL-K) responded selectively and significantly to the biperiden infusion. It is concluded that cholinergic activity might be involved in the regulation of affectivity in man.

Topics: Adult; Biperiden; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Placebos; Psychiatric Status Rating Scales; Time Factors

Aggressive behaviors can be considered symptoms of bipolar disorder, schizophrenia, post-traumatic stress, intermittent explosive, and personality disorders. Nociceptin/orphanin FQ (N/OFQ) is a peptide acting as endogenous ligand of the NOP receptor. Preclinical and clinical findings suggest the NOP receptor as an innovative target for the treatment of psychopathologies, such as anxiety, depression, and drug abuse. This study investigated the effects of NOP ligands and the behavioral phenotype of mice lacking the NOP receptor in an animal model of aggressiveness, the resident-intruder test. Mood stabilizers, such as valproate, lithium, and carbamazepine reduced aggressive behaviors of resident mice, while diazepam was inactive. In contrast, para-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, increased aggressiveness in mice. Similar to PCPA, the treatment with the NOP agonists Ro 65-6570 and AT-090 also increased aggressive behaviors. The systemic administration of the NOP antagonist SB-612111 did not modify the behavior of resident mice, but it prevented the aggressive behavior of Ro 65-6570. NOP receptor knockout mice did not display any behavioral difference compared to wild-type animals in the resident-intruder test. None of the treatments affected non-agonistic behaviors and spontaneous locomotion. In conclusion, NOP receptor agonists increased aggressiveness, while the pharmacological and genetic blockade of NOP receptor signaling did not modify agonistic behaviors. Ultimately, the aggressive profile of action of NOP agonists should be taken into account in the development of innovative psychiatric drugs targeting the NOP receptor.

Topics: Aggression; Agonistic Behavior; Animals; Anxiety; Bipolar Disorder; Carbamazepine; Cycloheptanes; Depression; Depressive Disorder; Disease Models, Animal; Fenclonine; Lithium; Male; Mice; Mice, Knockout; Nociceptin; Nociceptin Receptor; Opioid Peptides; Piperidines; Receptors, Opioid; Valproic Acid

This study aimed to investigate whether 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase inhibitor with anti-inflammatory effects, could alleviate spontaneous recurrent seizures (SRS) and epilepsy-associated depressive behaviours in the lithium chloride (LiCl)-pilocarpine-induced post-status epilepticus (SE) rat model.. The rats were intraperitoneally (IP) injected with LiCl (127 mg/kg) and pilocarpine (40 mg/kg) to induce SE. A video surveillance system was used to monitor SRS in the post-SE model for 6 weeks (from the onset of the 2nd week to the end of the 7th week after SE induction). TPPU (0.1 mg/kg/d) was intragastrically given for 4 weeks from the 21st day after SE induction in the SRS + 0.1 TPPU group. The SRS + PEG 400 group was given the vehicle (40% polyethylene glycol 400) instead, and the control group was given LiCl and PEG 400 but not pilocarpine. The sucrose preference test (SPT) and forced swim test (FST) were conducted to evaluate the depression-like behaviours of rats. Immunofluorescent staining, enzyme-linked immunosorbent assay, and western blot analysis were performed to measure astrocytic and microglial gliosis, neuronal loss, and levels of soluble epoxide hydrolase (sEH), cytokines [tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6], and cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB).. The frequency of SRS was significantly decreased at 6 weeks and 7 weeks after SE induction in the 0.1TPP U group compared with the SRS + PEG 400 group. The immobility time (IMT) evaluated by FST was significantly decreased, whereas the climbing time (CMT) was increased, and the sucrose preference rate (SPR) evaluated by SPT was in an increasing trend. The levels of sEH, TNF-α, IL-1β, and IL-6 in the hippocampus (Hip) and prefrontal cortex (PFC) were all significantly increased in the SRS + PEG 400 group compared with the control group; neuronal loss, astrogliosis, and microglial activation were also observed. The astrocytic and microglial activation and levels of the pro-inflammatory cytokines in the Hip and PFC were significantly attenuated in the TPPU group compared with the SRS + PEG 400 group; moreover, neuronal loss and the decreased CREB expression were significantly alleviated as well.. TPPU treatment after SE attenuates SRS and epilepsy-associated depressive behaviours in the LiCl-pilocarpine induced post-SE rat model, and it also exerts anti-inflammatory effects in the brain. Our findings suggest a new therapeutic approach for epilepsy and its comorbidities, especially depression.

Topics: Animals; Astrocytes; Brain; Depression; Depressive Disorder; Disease Models, Animal; Epilepsy; Epoxide Hydrolases; Hippocampus; Lithium Chloride; Male; Microglia; Neurons; Phenylurea Compounds; Pilocarpine; Piperidines; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus; Tumor Necrosis Factor-alpha

Short and long acting NMDA receptor (NMDAR) antagonists exert their antidepressant-like effects by activating signaling pathways involved in the synthesis of synaptic proteins and formation of new synaptic connections in the prefrontal cortex (PFC) of rats. The blockade of the ERK pathway abolishes ketamine and Ro 25-6981 antidepressant potency. However, the role of ERK in the antidepressant-like activity of short acting NMDAR antagonists is still unclear. More puzzling is the fact that the precise role of ERK in the short and long lasting effects of long-acting NMDAR antagonists is unknown. In this study, we show that zinc, (Zn) a short-acting NMDAR antagonist evokes only transient ERK activation, which is observed 7 min after its administration in the PFC of rats. In contrast to Zn, the long acting NMDAR antagonist Ro 25-6981 produces persistent ERK activation lasting up to 24 h. Pretreatment with the MAPK/ERK inhibitor (U0126) totally abolished Zn and Ro 25-6981 antidepressant-like activities in the forced swim test in rats. However, when U0126 is administered 15 min after Zn or Ro 25-6981 both compounds maintain their short-lasting antidepressant-like activity. On the other hand, posttreatment with U0126 significantly attenuated the long lasting antidepressant-like activity of Ro 25-6981. These results indicate that the activation of ERK is crucial for the short- and long lasting antidepressant-like activity observed in the FST in rats.

Topics: Animals; Antidepressive Agents; Aspartic Acid; Butadienes; Depressive Disorder; Disease Models, Animal; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Male; Motor Activity; Nitriles; Organometallic Compounds; Phenols; Phosphorylation; Piperidines; Prefrontal Cortex; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptosomes; Time Factors; Zinc Compounds

Pre-clinical and clinical studies indicated that a blockade of the NMDA receptor complex creates new opportunities for the treatment of affective disorders, including depression. The aim of the present study was to assess the influence of traxoprodil (10 mg/kg) on the activity of desipramine (10 mg/kg), paroxetine (0.5 mg/kg), milnacipran (1.25 mg/kg), and bupropion (10 mg/kg), each at sub-therapeutic doses. Moreover, brain levels of traxoprodil and tested agents were determined using HPLC. The obtained results were used to ascertain the nature of occurring interaction between traxoprodil and studied antidepressants. The experiment was carried out on naïve adult male Albino Swiss mice. Traxoprodil and other tested drugs were administered intraperitoneally. The influence of traxoprodil on the activity of selected antidepressants was evaluated in forced swim test (FST). Locomotor activity was estimated to exclude false positive/negative data. To assess the influence of traxoprodil on the concentration of used antidepressants, their levels were determined in murine brains using HPLC. Results indicated that traxoprodil potentiated activity of all antidepressants examined in FST and the observed effects were not due to the increase in locomotor activity. Only in the case of co-administration of traxoprodil and bupropion, increased bupropion concentrations in brain tissue were observed. All tested agents increased the traxoprodil levels in the brain. Administration of a sub-active dose of traxoprodil with antidepressants from different chemical groups, which act via enhancing monoaminergic transduction, caused the antidepressant-like effect in FST in mice. The interactions of traxoprodil with desipramine, paroxetine, milnacipran, and bupropion occur, at least partially, in the pharmacokinetic phase.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Brain; Bupropion; Chromatography, High Pressure Liquid; Cyclopropanes; Depressive Disorder; Desipramine; Disease Models, Animal; Drug Interactions; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Male; Mice; Milnacipran; Motor Activity; Paroxetine; Piperidines; Receptors, N-Methyl-D-Aspartate

The treatment of depression in old age is complicated by frequent co-morbidity with cognitive impairment. Anti-dementia drugs have some efficacy to improve cognitive performance and there is an inconsistent literature regarding the effect of such drugs on depressive symptoms. Here, we have investigated whether anti-dementia drugs would have antidepressant-like and pro-cognitive effects in a well-validated animal model of depression and cognitive impairment, chronic mild stress (CMS).. Rats were subjected to CMS for a total of 8 weeks. After 2 weeks, subgroups of stressed and non-stressed animals were treated daily, for 5 weeks followed by 1 week of drug withdrawal, with vehicle, imipramine (10 mg/kg), rivastigmine (2 mg/kg), donepezil (0.3 mg/kg) or memantine (5 mg/kg). Sucrose intake was tested weekly, and animals were also tested in the elevated plus maze (at week 7) and in an object recognition task (at weeks 7 and 8).. CMS decreased sucrose intake, had an anxiogenic effect in the elevated plus maze, and impaired performance in the object recognition test. Imipramine, rivastigmine and donepezil normalized performance in all three tests. Memantine had anxiolytic and pro-cognitive effects, but did not reverse CMS-induced anhedonia.. The fact that all three anti-dementia drugs reversed CMS-induced cognitive impairment and that cholinesterase inhibitors, but not memantine, have antidepressant-like effects in this model suggest that different mechanisms may underlie CMS-induced anhedonia and cognitive impairment. We discuss the clinical implications of these findings.

Topics: Anhedonia; Animals; Antidepressive Agents; Cholinesterase Inhibitors; Cognitive Dysfunction; Depressive Disorder; Disease Models, Animal; Donepezil; Indans; Male; Nootropic Agents; Piperidines; Rats; Rats, Wistar; Recognition, Psychology; Rivastigmine; Stress, Psychological

The aim was to evaluate the clinical profile and effectiveness of ECT in women. A retrospective chart review was carried out to identify female patients who had received ECT during the period September 2013-February 2015. Details regarding their sociodemographic, clinical, and treatment data were extracted from these records for the present study. The total number of patients, admitted to our psychiatry inpatient clinic during the survey period, was 802. During this period, 26 (3.24 %) female patients received ECT. Patients who received ECT were mostly in age group of 25-44 years (76.9 %). Twenty percent of patients were in the postpartum period. Psychotic disorders (46.1 %) was the most common diagnosis for which ECT was used, followed by bipolar affective disorder, current episode manic (19.2 %). At the end of ECT courses, 70 % of the patients showed good response with a CGI-I of 1 or 2, and 30 % showed minimal response with a CGI-I score of 3. The most common side effects were post-ECT confusion (15.4 %) and prolonged seizure (11.5 %). This rate of prolonged seizure was higher the rates reported in the literature. The bronchospasm related with remifentanil, post-ECT bradycardia, hypertensive crisis and oligohydramnios were also reported in one case each. ECT is a safe and effective treatment option in women with severe psychiatric disorders and disorders in the perinatal/postpartum period are a major area of ECT use. The female gender may be a contributing factor for the higher rates of prolonged seizure.

Topics: Adult; Aged; Anesthetics, Intravenous; Bipolar Disorder; Bradycardia; Bronchial Spasm; Depression, Postpartum; Depressive Disorder; Electroconvulsive Therapy; Female; Hospitals, Psychiatric; Humans; Hypertension; Middle Aged; Oligohydramnios; Piperidines; Pregnancy; Pregnancy Complications; Psychotic Disorders; Puerperal Disorders; Remifentanil; Retrospective Studies; Treatment Outcome; Turkey; Young Adult

Pharmacological and genetic evidence support antidepressant-like effects elicited by the blockade of the NOP receptor. The learned helplessness (LH) model employs uncontrollable and unpredictable electric footshocks as a stressor stimulus to induce a depressive-like phenotype that can be reversed by classical antidepressants.. The present study aimed to evaluate the action of NOP receptor antagonists in helpless mice.. Male Swiss mice were subjected to the three steps of the LH paradigm (i.e., (1) induction, (2) screening, and (3) test). Only helpless animals were subjected to the test session. During the test session, animals were placed in the electrified chamber and the latency to escape after the footshock and the frequency of escape failures were recorded. The effect of the following treatments administered before the test session were evaluated: nortriptyline (30 mg/kg, ip, 60 min), fluoxetine (30 mg/kg, ip, four consecutive days of treatment), and NOP antagonists SB-612111 (1-10 mg/kg, ip, 30 min) and UFP-101 (1-10 nmol, icv, 5 min). To rule out possible biases, the effects of treatments on controllable stressful and non stressful situations were assessed.. In helpless mice, nortriptyline, fluoxetine, UFP-101 (3-10 nmol), and SB-612111 (3-10 mg/kg) significantly reduced escape latencies and escape failures. No effects of drug treatments were observed in mice subjected to the controllable electric footshocks and non stressful situations.. Acute treatment with NOP antagonists reversed helplessness similarly to the classical antidepressants. These findings support the proposal that NOP receptor antagonists are worthy of development as innovative antidepressant drugs.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Cycloheptanes; Depressive Disorder; Disease Models, Animal; Fluoxetine; Helplessness, Learned; Male; Mice; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Nortriptyline; Opioid Peptides; Piperidines; Receptors, Opioid; Signal Transduction

The main objective of our study was to evaluate the influence of traxoprodil on the activity of the atypical antidepressant drugs (agomelatine, mianserin, tianeptine).. The forced swim test (FST) in mice was used to determine the antidepressant-like activity of the tested agents. Drugs levels in brain tissue were assessed by a high performance liquid chromatography method.. Concurrent intraperitoneal administration of per se ineffective doses of traxoprodil (10mg/kg) and agomelatine (20mg/kg) shortened the immobility time of animals in the FST. The observed effect was associated with elevated brain levels of traxoprodil. Similar interaction was not detected for traxoprodil and mianserin (10mg/kg) or tianeptine (15mg/kg).. Traxoprodil-agomelatine interaction is pharmacokinetic in nature. A combination of these agents has a potential to become an interesting strategy in the treatment of depression.

Topics: Acetamides; Animals; Antidepressive Agents; Brain; Depression; Depressive Disorder; Drug Synergism; Male; Mianserin; Mice; Motor Activity; Piperidines; Swimming; Thiazepines

The purpose of the experiments was to explore the role of the endocannabinoid system, through cannabinoid (CB) receptor ligands, nicotine and scopolamine, in the depression-related responses using the forced swimming test (FST) in mice. Our results revealed that acute injection of oleamide (10 and 20 mg/kg), a CB1 receptor agonist, caused antidepressant-like effect in the FST, while AM 251 (0.25-3 mg/kg), a CB1 receptor antagonist, did not provoke any effect in this test. Moreover, acute administration of both CB2 receptor agonist, JWH 133 (0.5 and 1 mg/kg) and CB2 receptor antagonist, AM 630 (0.5 mg/kg), exhibited antidepressant action. Antidepressant effects of oleamide and JWH 133 were attenuated by acute injection of both non-effective dose of AM 251, as well as AM 630. Among the all CB compounds used, only the combination of non-effective dose of oleamide (2.5 mg/kg) with non-effective dose of nicotine (0.5 mg/kg) caused an antidepressant effect. However, none of the CB receptor ligands, had influence on the antidepressant effects provoked by nicotine (0.2 mg/kg) injection. In turn, the combination of non-effective dose of oleamide (2.5 mg/kg); JWH (2 mg/kg) or AM 630 (2 mg/kg), but not of AM 251 (0.25 mg/kg), with non-effective dose of scopolamine (0.1 mg/kg), exhibited antidepressant properties. Indeed, all of the CB compounds used, intensified the antidepressant-like effects induced by an acute injection of scopolamine (0.3 mg/kg). Our results provide clear evidence that the endocannabinoid system participates in the depression-related behavior and through interactions with cholinergic system modulate these kind of responses.

Topics: Animals; Antidepressive Agents; Cannabinoids; Depressive Disorder; Disease Models, Animal; Indoles; Ligands; Male; Mice; Motor Activity; Nicotine; Oleic Acids; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Scopolamine; Swimming

Drugs targeting the glutamate N-methyl-d-aspartate receptor (NMDAR) may be efficacious for treating mood disorders, as exemplified by the rapid antidepressant effects produced by single administration of the NMDAR antagonist ketamine. Though the precise mechanisms underlying the antidepressant-related effects of NMDAR antagonism remain unclear, recent studies implicate specific NMDAR subunits, including GluN2A and GluN2B, as well as the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) subunit glutamate receptor interacting molecule, PSD-95. Here, integrating mutant and pharmacological in mice, we investigated the contribution of these subunits and molecules to antidepressant-related behaviors and the antidepressant-related effects of the GluN2B blocker, Ro 25-6981. We found that global deletion of GluA1 or PSD-95 reduced forced swim test (FST) immobility, mimicking the antidepressant-related effect produced by systemically administered Ro 25-6981 in C57BL/6J mice. Moreover, the FST antidepressant-like effects of systemic Ro 25-6981 were intact in mutants with global GluA1 deletion or GluN1 deletion in forebrain interneurons, but were absent in mutants constitutively lacking GluN2A or PSD-95. Next, we found that microinfusing Ro 25-6981 into the medial prefrontal cortex (mPFC), but not basolateral amygdala, of C57BL/6J mice was sufficient to produce an antidepressant-like effect. Together, these findings extend and refine current understanding of the mechanisms mediating antidepressant-like effects produced by NMDAR-GluN2B antagonists, and may inform the development of a novel class of medications for treating depression that target the GluN2B subtype of NMDAR.

Topics: Amygdala; Animals; Antidepressive Agents; Depressive Disorder; Disks Large Homolog 4 Protein; Excitatory Amino Acid Antagonists; Guanylate Kinases; Interneurons; Male; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Phenols; Piperidines; Prefrontal Cortex; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work in naive rats showed that 5-HT₄ receptor agonists had rapid effects on depression-related behaviors and on hippocampal neurogenesis. We decided to investigate whether 5-HT₄ receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression, and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT₄ receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety- and depression-related behaviors, as well as on hippocampal neurogenesis in comparison with chronic fluoxetine treatment (18 mg/kg/day). Then, using our anxiety/depression model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7 days) or chronic (28 days) RS67333 treatment. We also assessed whether a 5-HT₄ receptor antagonist (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis, specifically facilitating maturation of newborn neurons. However, unlike fluoxetine, anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT₄ receptor activation is necessary for these effects of SSRIs. 5-HT₄ receptor stimulation could represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.

Topics: Aniline Compounds; Animals; Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Anxiety; Comorbidity; Corticosterone; Depressive Disorder; Disease Models, Animal; Fluoxetine; Hippocampus; Indoles; Male; Mice; Mice, Inbred C57BL; Neurogenesis; Neurons; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Sulfonamides; Time Factors

Although the serotonergic system has been implicated in healthy as well as in pathological emotional states, knowledge about its involvement in personality is limited. Earlier research on this topic suggests that post-synaptic 5-HT2A receptors could be involved in particular in frontal cortical areas. In drug-naïve healthy individuals, we examined the relationship between these 5-HT2A receptors and the temperament dimension harm avoidance (HA) using 123I-5-I-R91150 single photon emission computed tomography (SPECT). HA is a personality feature closely related to stress, anxiety and depression proneness, and it is thought to be mediated by the serotonergic system. We focused on the prefrontal cortices as these regions are frequently implicated in cognitive processes related to a variety of affective disorders. We found a positive relationship between dorsal prefrontal cortical (DPFC) 5-HT2A receptor binding indices (BI) and individual HA scores. Further, our results suggest that those individuals with a tendency to worry or to ruminate are particularly prone to display significantly higher 5-HT2A receptor BI in the left DPFC. Although we only examined psychologically healthy individuals, this relationship suggests a possible vulnerability for affective disorders.

Topics: Adolescent; Adult; Aged; Anxiety; Depressive Disorder; Female; Harm Reduction; Humans; Male; Middle Aged; Personality Disorders; Piperidines; Prefrontal Cortex; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Temperament; Tomography, Emission-Computed, Single-Photon; Young Adult

Multiple pre-clinical and clinical studies clearly displayed implication of the NMDA receptors in development of depressive disorders since a variety of NMDA receptor antagonists exhibit an antidepressant-like effect. The main aim of our study was to assess the influence of ifenprodil - an allosteric modulator selectively binding at the NR2B subunit on the performance in the forced swim test in mice of various NMDA receptor ligands interacting with distinct components of the NMDA receptor complex. Ifenprodil at a dose of 10mg/kg enhanced the antidepressant-like effect of CGP 37849 (a competitive NMDA receptor antagonist, 0.312mg/kg), L-701,324 (an antagonist at glycine site, 1mg/kg), MK-801 (a non-competitive antagonist, 0.05mg/kg) and d-cycloserine (a partial agonist of a glycine site, 2.5mg/kg) but it did not shorten the immobility time of animals which concurrently received an inorganic modulator of the NMDA receptor complex, such as Zn(2+) (2.5mg/kg) or Mg(2+) (10mg/kg). On the other hand, the antidepressant-like effect of ifenprodil (20mg/kg) was reversed by N-methyl-d-aspartic acid (an agonist at the glutamate site, 75mg/kg) or d-serine (an agonist at the glycine site, 100nmol/mouse). In conclusion, the antidepressant-like potential of ifenprodil given concomitantly with NMDA ligands was either reinforced (in the case of both partial agonist and antagonists, except for magnesium and zinc) or diminished (in the case of conventional full agonists).

Topics: Animals; Antidepressive Agents; Depressive Disorder; Dose-Response Relationship, Drug; Ligands; Male; Mice; Motor Activity; Piperidines; Receptors, N-Methyl-D-Aspartate; Swimming; Treatment Outcome

Quite a number of patients diagnosed with major depression are resistant to several well carried-out psychopharmacological interventions. It remains unclear as to how the serotonergic system is implicated in the phenomenon of treatment-resistance.. We examined the involvement of post-synaptic 5-HT(2A) receptors in the pathophysiology of treatment-resistance in unipolar melancholic major depression with (123)I-5-I-R91150 SPECT. 15 antidepressant-naïve (ADN) first-episode depressed patients, 15 antidepressant-free treatment-resistant depressed (TRD) patients and 15 never-depressed individuals, matched for age and gender were studied.. Compared to ADN patients and healthy controls, TRD patients displayed significantly lower 5-HT(2A) receptor binding index (BI) in the dorsal regions of the prefrontal and the anterior cingulate cortex. No significant 5-HT(2A) receptor BI differences between ADN patients and controls were observed.. At the cortical level, 5-HT(2A) receptor BI does not significantly differ in first-episode melancholic depressed patients compared to healthy controls. This observation might imply a limited short-term impact on the serotonergic system in first episode depression. Our results also suggest that when encountered with treatment-resistance, the 5-HT(2A) receptors in the DPFC-ACC axis are significantly down-regulated. However, whether this assumed underlying pathophysiological mechanism is due solely to abnormalities in the serotonergic system remains to be answered. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Topics: Adult; Analysis of Variance; Brain Mapping; Depressive Disorder; Female; Gyrus Cinguli; Humans; Iodine Isotopes; Male; Middle Aged; Piperidines; Prefrontal Cortex; Probability; Receptor, Serotonin, 5-HT2A; Tomography, Emission-Computed, Single-Photon

Electroconvulsive therapy is safe and effective in the treatment of depression in older individuals. Minor cognitive side effects of electroconvulsive therapy include acute postictal confusion and reversible short-term memory deficits. However, interictal delirium is uncommon in absence of risk factors. Herein, we report the case a depressed male patient without any known risk factors who developed interictal delirium 2 days after his sixth electroconvulsive therapy session. Interictal delirium improved with treatment within 1 week.

Topics: Cholinesterase Inhibitors; Delirium; Depressive Disorder; Donepezil; Electroconvulsive Therapy; Follow-Up Studies; Haloperidol; Humans; Hypnotics and Sedatives; Indans; Lorazepam; Male; Middle Aged; Piperidines; Risk Factors; Time Factors

A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK(1) receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK(1) receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.

Topics: Animals; Behavior, Animal; Brain; CHO Cells; Cricetinae; Cricetulus; Depressive Disorder; Drug Discovery; Gerbillinae; Half-Life; Humans; Magnetic Resonance Spectroscopy; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Regression Analysis; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Infrared; Stereoisomerism

To provide feedback on the initial market authorization of rimonabant, a drug to be used under strict guidelines, we conducted a study with information from the National health insurance reimbursements database for southeastern France. The aims of this study were to: (1) describe the characteristics of subjects who have had one rimonabant prescription reimbursed; (2) study the frequency of prescriptions that did not comply with reimbursement criteria; (3) study the frequency of prescriptions for patients simultaneously treated with antidepressants; and (4) analyse the factors associated with both types of prescription (patient and prescriber characteristics).. Using the database of drug reimbursements maintained by the southeastern France general health insurance fund, we studied the characteristics of outpatients with at least one reimbursement for rimonabant, compared them to the rest of the population, and analysed compliance with the indications, contraindications, and regulations for rimonabant prescription with multivariate logistic regressions.. A total of 10,510 beneficiaries (0.28%) had at least one rimonabant reimbursement. Among them, 55.7% were treated for diabetes. For at least 62.4% of rimonabant beneficiaries, the reimbursement regulations were not respected: this was significantly more frequent among women less than 57 years old, subjects with no chronic diseases, and when the prescriber was not an endocrinologist; 11.4% of rimonabant beneficiaries also received an antidepressant treatment.. Despite the specific status of rimonabant regarding its reimbursement modalities, these results suggest that some prescribers get around reimbursement instructions and that a significant percentage of prescriptions did not respect an important contraindication. Tools to follow up the prescriptions of new drugs with strict guidelines for use should be developed and physicians should be better informed and trained regarding specific prescription regulations.

Topics: Adult; Antidepressive Agents; Body Mass Index; Depressive Disorder; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Prescriptions; Feedback; Female; France; Humans; Insurance, Health, Reimbursement; Logistic Models; Male; Middle Aged; Obesity; Piperidines; Practice Guidelines as Topic; Pyrazoles; Retrospective Studies; Rimonabant

Marketing authorization for rimonabant was withdrawn in October 2008, mainly because the psychiatric adverse effects could not be addressed by further risk minimization.. The aim of the study was to compare the risk of major and minor depressive episodes in the 6 months prior to and the 6 months after starting treatment with rimonabant.. We conducted a before and after study using the observational cohort technique of Modified Prescription Event Monitoring to compare the risk of major and minor depressive episodes in new users of rimonabant reported in the 6 months before to the 6 months after starting treatment with rimonabant. Patients were identified from dispensed prescriptions issued by primary care physicians from June 2006 to October 2008. Patient demographics and information on depressive episodes were requested 6 months after the date of the first prescription for each patient. Risk ratios (RR) were calculated by comparing before and after events using a matched analysis.. The cohort comprised 10,011 patients. The number of patients who had major depressive episodes before and after starting treatment were 147 and 168, respectively (RR 1.14; 95% CI 0.94, 1.39) and the number of patients who had minor depressive episodes were 825 and 829, respectively (RR 1.00; 95% CI 0.93, 1.10). For patients who had a previous history of psychiatric illness (n = 1132), 91 and 73, respectively, experienced major depressive episodes (RR 0.80; 95% CI 0.62, 1.03), and 367 and 220, respectively, experienced minor depressive episodes (RR 0.59; 95% CI 0.53, 0.68). For patients without a previous history of psychiatric illness (n = 8879), 56 and 95, respectively, experienced major depressive episodes (RR 1.7; 95% CI 1.2, 2.3), and 458 and 609, respectively, experienced minor depressive episodes (RR 1.33; 95% CI 1.20, 1.48).. When comparing all patients in the cohort, there was no increased risk of developing a depressive episode whilst taking rimonabant. However, when considering subsets of patients with and without a previous history of psychiatric illness, the risk profiles were different. In patients without a previous history of psychiatric illness, there were more depressive episodes in the 6 months after starting treatment compared with the 6 months before starting treatment with rimonabant.

Topics: Adult; Cohort Studies; Depressive Disorder; England; Female; Humans; Male; Middle Aged; Physicians, Primary Care; Piperidines; Prescriptions; Pyrazoles; Rimonabant; Risk Factors

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Depressive Disorder; Disease Progression; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

Although often providing more reliable and informative findings relative to other study designs, longitudinal investigations of prevalence and predictors of suicidal behaviour remain uncommon. This paper compares 12-month prevalence rates for suicidal ideation and suicide attempt at baseline and follow-up; identifies new cases and remissions; and assesses the capacity of baseline data to predict serious suicidality at follow-up, focusing on age and gender differences.. 6,666 participants aged 20-29, 40-49 and 60-69 years were drawn from the first (1999-2001) and second (2003-2006) waves of a general population survey. Analyses involved multivariate logistic regression.. At follow-up, prevalence of suicidal ideation and suicide attempt had decreased (8.2%-6.1%, and 0.8%-0.5%, respectively). However, over one quarter of those reporting serious suicidality at baseline still experienced it four years later. Females aged 20-29 never married or diagnosed with a physical illness at follow-up were at greater risk of serious suicidality (OR = 4.17, 95% CI = 3.11-5.23; OR = 3.18, 95% CI = 2.09-4.26, respectively). Males aged 40-49 not in the labour force had increased odds of serious suicidality (OR = 4.08, 95% CI = 1.6-6.48) compared to their equivalently-aged and employed counterparts. Depressed/anxious females aged 60-69 were nearly 30% more likely to be seriously suicidal.. There are age and gender differentials in the risk factors for suicidality. Life-circumstances contribute substantially to the onset of serious suicidality, in addition to symptoms of depression and anxiety. These findings are particularly pertinent to the development of effective population-based suicide prevention strategies.

Topics: Adult; Age Distribution; Age Factors; Aged; Azepines; Cause of Death; Data Collection; Depressive Disorder; Female; Follow-Up Studies; Health Status; Humans; Longitudinal Studies; Male; Mental Disorders; Middle Aged; Piperidines; Prevalence; Risk Factors; Sex Factors; Suicide; Suicide, Attempted

Topics: Anti-Obesity Agents; Cardiovascular Agents; Cardiovascular Diseases; Depressive Disorder; Drug Approval; Europe; Humans; Multicenter Studies as Topic; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Suicide; Treatment Failure

Topics: Anti-Obesity Agents; Cardiovascular Agents; Cardiovascular Diseases; Cytochrome P-450 CYP2D6; Depressive Disorder; Europe; Humans; Multicenter Studies as Topic; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Research Design; Rimonabant; Suicide; Treatment Failure

Curcumin, a yellow pigment extracted from rhizomes of the plant Curcuma longa (turmeric), has been widely used as food additive and also as a herbal medicine throughout Asia. The present study was designed to study the pharmacological, biochemical and neurochemical effects of daily administration of curcumin to rats subjected to chronic unpredictable stress. Curcumin treatment (20 and 40 mg/kg, i.p., 21 days) significantly reversed the chronic unpredictable stress-induced behavioral (increase immobility period), biochemical (increase monoamine oxidase activity) and neurochemical (depletion of brain monoamine levels) alterations. The combination of piperine (2.5 mg/kg, i.p., 21 days), a bioavailability enhancer, with curcumin (20 and 40 mg/kg, i.p., 21 days) showed significant potentiation of its anti-immobility, neurotransmitter enhancing (serotonin and dopamine) and monoamine oxidase inhibitory (MAO-A) effects as compared to curcumin effect per se. This study provided a scientific rationale for the use of curcumin and its co-administration with piperine in the treatment of depressive disorders.

Topics: Alkaloids; Animals; Antidepressive Agents; Behavior, Animal; Benzodioxoles; Biogenic Amines; Biological Availability; Biomarkers; Brain Chemistry; Chronic Disease; Cold Temperature; Curcumin; Depressive Disorder; Female; Light; Monoamine Oxidase; Motor Activity; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Stress, Psychological; Swimming

Topics: Affect; Anti-Obesity Agents; Antidepressive Agents; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Depression; Depressive Disorder; Endocannabinoids; Humans; Ligands; Obesity; Piperidines; Pyrazoles; Research; Rimonabant; Signal Transduction; Tobacco Use Disorder

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Depressive Disorder; Humans; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Risk

The present study was made to investigate the role of tachykinin NK2 receptors in the expression of stress-related behaviors in animals. Under basal conditions, intraperitoneal (i.p.) administration of the selective tachykinin NK2 receptor antagonist, saredutant (1 and 3 mg/kg) or diazepam (1 mg/kg) exerted anxiolytic-like effects in rodents, as they reduced grooming score of Wistar male rats tested in the novelty-induced grooming sampling test (NGT) and increased percentage of time and entries in open arms of Swiss male mice tested in the elevated plus maze (EPM) test. After previous exposure to stress-related conditions, as induced by a 2-min forced swim made 5 min prior to the EPM test, saredutant but not diazepam, exhibited anxiolytic-like effects in mice. To study the antidepressant-like activity of tachykinin NK2 receptor antagonist under basal conditions, different groups of rats were injected i.p. with saredutant (2.5, 5 and 10 mg/kg) or the tricyclic antidepressant, clomipramine (50 mg/kg) and tested in the forced swim test (FST), a widely used antidepressant-responsive test. The influence of stress-related conditions was studied in rats subjected to electric foot-shocks (1 mA, 1 s) 24, 5 and 1 h prior to FST, after drugs injection. In the FST, clomipramine decreased the immobility time only under basal conditions, but not after application of acute foot-shocks. To the contrary, saredutant-treated rats also exhibited more active behavior in FST after previous exposure to stressors. These results give further support to the hypothesis that tachykinin NK2 receptors may be a therapeutic target for pharmacological treatment of stress-related diseases, such as anxiety and depression.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents, Tricyclic; Anxiety; Behavior, Animal; Benzamides; Clomipramine; Depressive Disorder; Diazepam; Electroshock; Grooming; Male; Mice; Mood Disorders; Motor Activity; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-2; Stress, Psychological; Swimming

Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action.

Topics: Aniline Compounds; Animals; Antidepressive Agents; Brain; Cyclic AMP Response Element-Binding Protein; Depressive Disorder; Disease Models, Animal; Hippocampus; Male; Motor Activity; Phosphorylation; Piperidines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin, 5-HT4; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Stress, Psychological; Time Factors

The aim of this study was to validate melanin-concentrating hormone (MCH)-1 receptor antagonism as a potential treatment of mood disorders. We attempted to replicate the effects previously reported with SNAP-7941 and expanded the investigation to three other orally bioavailable MCH-1 receptor antagonists with good brain penetration. SNAP-7941 (3-30 mg/kg, i.p.) and T-226296 (5-60 mg/kg, p.o.) (+/- racemate), were evaluated in the rat forced swim and mouse tail suspension tests. (+)SNAP-7941 (3-10 mg/kg, p.o.) was also tested in a modified 5-min rat forced swim protocol as previously reported. A-665798 (3-30 mg/kg, p.o.) and A-777903 (3-30 mg/kg, p.o.) were tested in mouse tail suspension and rat Vogel tests. None of the compounds showed meaningful efficacy in the paradigms tested. The lack of efficacy with four structurally different MCH-1 receptor antagonists does not support a role for therapeutic treatment of depression/anxiety via this mechanism of action.

Topics: Analysis of Variance; Animals; Anxiety; Benzopyrans; Biphenyl Compounds; Conflict, Psychological; Depressive Disorder; Disease Models, Animal; Hindlimb Suspension; Indazoles; Male; Mice; Mice, Inbred BALB C; Motor Activity; Naphthalenes; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Somatostatin; Swimming

Substance P antagonists of the neurokinin-1 receptor type (NK1) have growing interest as new antidepressant therapies. It has been postulated that these drugs exert this putative therapeutic effect without direct interactions with serotonin (5-HT) neurons. In line with this assumption, previous intracerebral in vivo microdialysis experiments provided evidence that the NK1 receptor antagonists did not change basal cortical 5-HT levels. However, we found that increases in cortical 5-HT overflow caused by systemic injection of the selective serotonin reuptake inhibitor (SSRI), paroxetine was higher in freely moving (C57BL/6x129sv) NK1-/- mutants than in wild-type NK1+/+ mice. More recently, a pharmacological study has led to a similar conclusion since GR205171, a NK1 receptor antagonist, potentiated paroxetine-induced increases in cortical 5-HT dialysate following its acute systemic or intra-raphe administration to wild-type mice . In the present study, we tested whether an acute combination of SSRI and NK1 receptor antagonist could display antidepressant-like activity using the forced swimming test in Swiss mice. We found that a single systemic dose of GR205171 (10 and 30 mg/kg, i.p.) had no effect by itself. However, it selectively potentiated the antidepressant-like activity of subactive doses of two serotonergic antidepressant drugs, citalopram and paroxetine (without psychomotor stimulant activity), but not that of noradrenaline reuptake inhibitor, desipramine. In agreement with neurochemical data, the present study confirms that co-administration of a NK1 receptor antagonist with an antidepressant drug such as a SSRI may have a therapeutic potential to improve the treatment of major depressive episodes in human compared to SSRI alone.

Topics: Adrenergic Uptake Inhibitors; Analysis of Variance; Animals; Antidepressive Agents; Citalopram; Depressive Disorder; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Escape Reaction; Male; Mice; Neurokinin-1 Receptor Antagonists; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Selective Serotonin Reuptake Inhibitors; Stress, Psychological; Swimming; Tetrazoles

A previous positron emission tomography (PET) study reported increased serotonin 5-HT(2A) receptor binding in unmedicated depressed patients with high scores on the Dysfunctional Attitudes Scale. The purpose of the present study was to use the highly selective 5-HT(2A) receptor ligand [(11)C]MDL 100,907 in a PET imaging paradigm to assess 1) 5-HT(2A) receptor binding potential in euthymic subjects with a history of recurrent depression and 2) the relationship between receptor binding and scores on the Dysfunctional Attitudes Scale.. Cortical 5-HT(2A) receptor binding was measured in 20 unmedicated, fully recovered unipolar depressed patients and 20 age- and gender-matched comparison subjects. Regional estimates of binding potential were obtained using a reversible plasma input function compartmental model and the cerebellum as a reference region to estimate the free and non-specifically bound [(11)C]MDL 100,907 in brain tissue.. Relative to the comparison subjects, the recovered depressed patients demonstrated significantly higher 5-HT(2A) receptor binding potential in the frontal cortex (mean increase: 19%), parietal cortex (mean increase: 25%), and occipital cortex (mean increase: 19%). 5-HT(2A) receptor binding potential correlated negatively with age in both patients and comparison subjects and positively with the Dysfunctional Attitudes Scale in the recovered patients.. These findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT(2A) receptors. The correlation of increased 5-HT(2A) receptor binding potential with increased scores on Dysfunctional Attitudes Scale supports earlier work suggesting that increased 5-HT(2A) receptor availability characterizes a group of depressed patients with high levels of dysfunctional attitudes.

Topics: Adult; Attitude; Carbon Radioisotopes; Cerebellum; Cerebral Cortex; Depressive Disorder; Female; Fluorobenzenes; Humans; Male; Personality Inventory; Piperidines; Positron-Emission Tomography; Psychiatric Status Rating Scales; Receptor, Serotonin, 5-HT2A; Recurrence; Tissue Distribution

NMDA receptors play a role in the aetiology of depression with non-competitive NMDA receptor antagonists such as amantadine showing synergy with conventional antidepressants. To advance a neurochemical rational for these findings, we have studied the effects of administration of amantadine and budipine with the antidepressants reboxetine (REB), paroxetine (PAROX) and clomipramine (CLOM) on extracellular DA in rats using microdialysis. Acutely, amantadine (40 mg/kg) or budipine (10 mg/kg) did not significantly alter extracellular DA. REB (10 mg/kg), PAROX (10 mg/kg) both increased cortical DA while CLOM (10 mg/kg) produced a decrease. When amantadine or budipine was administered 30 min before the antidepressants, DA increases were markedly greater than following the antidepressants alone. Chronically drug effects were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular DA at any time. The three antidepressants elicited a gradual increase in DA which became significant after 7 days and tended to plateau thereafter. When amantadine (20 mg/kg) or budipine (5 mg/kg) was co-administered with the three antidepressants, two differences were seen compared with the antidepressants alone. Firstly, the time required for significant increases in cortical DA was reduced with elevated levels now being observed by 4 days. Secondly, the increase in extracellular DA was greater in these rats throughout the experiment. If increased extracellular DA represents a step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants and possibly enhance their efficacy.

Topics: Amantadine; Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Depressive Disorder; Dopamine; Drug Interactions; Excitatory Amino Acid Antagonists; Extracellular Fluid; Frontal Lobe; Glutamic Acid; Male; Microdialysis; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Selective Serotonin Reuptake Inhibitors; Up-Regulation

The affinity of several antidepressant and antipsychotic drugs for the 5-HT7 receptor and its CNS distribution suggest potential in the treatment of psychiatric diseases. However, there is little direct evidence of receptor function in vivo to support this. We therefore evaluated 5-HT7 receptors as a potential drug target by generating and assessing a 5-HT7 receptor knockout mouse. No difference in assays sensitive to potential psychotic or anxiety states was observed between the 5-HT7 receptor knockout mice and wild type controls. However, in the Porsolt swim test, 5-HT7 receptor knockout mice showed a significant decrease in immobility compared to controls, a phenotype similar to antidepressant treated mice. Intriguingly, treatment of wild types with SB-258719, a selective 5-HT7 receptor antagonist, did not produce a significant decrease in immobility unless animals were tested in the dark (or active) cycle, rather than the light, adding to the body of evidence suggesting a circadian influence on receptor function. Extracellular recordings from hypothalamic slices showed that circadian rhythm phase shifts to 8-OH-DPAT are attenuated in the 5-HT7 receptor KO mice also indicating a role for the receptor in the regulation of circadian rhythms. These pharmacological and genetic knockout studies provide the first direct evidence that 5-HT7 receptor antagonists should be investigated for efficacy in the treatment of depression.

Topics: Animals; Depressive Disorder; Gene Targeting; Immobilization; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Receptors, Serotonin; Reflex, Startle; Serotonin Antagonists; Sulfonamides

Topics: Aged; Cholinesterase Inhibitors; Combined Modality Therapy; Depressive Disorder; Donepezil; Electroconvulsive Therapy; Humans; Indans; Male; Piperidines

The electroconvulsive therapy (ECT) service at West Virginia University conducted a retrospective analysis of 24 patients who received bilateral ECT between November 1998 and December 2003. Patients were treated with a standard methohexital-based anesthetic. Twenty-four patients became completely or relatively refractory to maximum settings on the ECT device and were then switched to remifentanil as the sole induction agent. Seizure threshold was established by stimulus dose retitration. Stimulus dose in total charge (mC) and dynamic energy (J) was significantly lower with the remifentanil anesthetic versus methohexital. (P < 0.0001) Resulting motor and EEG seizure duration in patients was significantly longer receiving the remifentanil anesthetic versus methohexital. (P < 0.0001) Previous reports describe a rise in seizure threshold in patients for repeated ECT. Although this rise occurred during the treatment course using a methohexital anesthetic, this effect was greatly diminished when remifentanil was used as the sole anesthetic agent. We conclude that remifentanil can provide improved seizure response to ECT in patients who are refractory to seizure induction after a standard methohexital anesthetic. We also conclude that the increase in stimulus dose typically required with repeated treatments is related to the anesthetic regimen.

Topics: Aged; Anesthetics, Intravenous; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Male; Methohexital; Middle Aged; Piperidines; Regression Analysis; Remifentanil; Retrospective Studies

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Awareness; Cholinesterase Inhibitors; Delusions; Depressive Disorder; Donepezil; Female; Humans; Indans; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Sick Role

Topics: Antidepressive Agents, Second-Generation; Cisapride; Cyclohexanols; Depressive Disorder; Gastrointestinal Agents; Humans; Nausea; Piperidines; Venlafaxine Hydrochloride

We have previously found that a cognition enhancer [(+)-5-oxo-D-prolinepiperidinamide monohydrate] (NS-105) reversed the inhibition of cyclic AMP formation induced by the GABA(B) receptor agonist baclofen. The GABA(B) receptor has been implicated in the pathophysiology of depressive illness. The present experiment was designed to evaluate the antidepressant activity of NS-105 in the forced swimming and learned helplessness tests in rats. NS-105 (1-100 mg/kg, p.o.) significantly decreased immobility time in the forced swimming test, an effect similar to that of desipramine. Repeated administration of NS-105 also reversed the failure to escape in the shuttle-box test of rats previously exposed to inescapable footshock. Biochemical data showed that repeated administration of NS-105 increased the number of GABA(B) receptors in rat cerebral cortex without affecting the binding properties of beta-adrenoceptors and 5-HT2 receptors. In contrast to other antidepressants, NS-105 did not inhibit monoamine uptake in vitro, nor did it change monoamine concentrations in brain tissues or extracellular fluids. These findings suggest that NS-105, which lacks an effect on monoaminergic systems, has potent antidepressant activity, which may involve up-regulation of GABA(B) receptors after repeated administration.

Topics: Animals; Antidepressive Agents; Cerebral Cortex; Depressive Disorder; Male; Microdialysis; Norepinephrine; Piperidines; Proline; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Receptors, GABA-B; Receptors, Serotonin; Serotonin; Synaptosomes

Topics: Adult; Antipsychotic Agents; Comorbidity; Depressive Disorder; Drug Therapy, Combination; Fluoxetine; Humans; Isoxazoles; Male; Obsessive-Compulsive Disorder; Piperidines; Risperidone; Tourette Syndrome; Treatment Outcome

Topics: Antipsychotic Agents; Bipolar Disorder; Depressive Disorder; Humans; Isoxazoles; Piperidines; Risperidone

Topics: Adult; Antipsychotic Agents; Clonazepam; Depressive Disorder; Drug Therapy, Combination; Humans; Isoxazoles; Male; Patient Readmission; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

Women with bulimia nervosa undergoing treatment with the reversible monoamine oxidase type A inhibitor, brofaromine, were rated for mood and eating behaviour and their plasma and urine were assessed for phenylacetic acid (unconjugated and total) and unconjugated phenylethylamine prior to and after four weeks of drug treatment. Changes in plasma unconjugated phenylacetic acid concentrations were significantly and negatively correlated with the corresponding changes in Hamilton Depression scores but not with eating behavior measures. There were no significant correlations between changes in phenylethylamine levels and changes in rating scores. Patients diagnosed as suffering concurrently from severe depression (Hamilton Depression score of 17 or higher) had lower plasma and urinary phenylacetic acid levels than did those whose depression was not severe (Hamilton score less than 17). Phenylethylamine concentrations were not different between the severely and mildly depressed subgroups. The results confirm earlier studies on the relationship between phenylacetic acid and depression while showing that a similar relationship does not pertain to phenylacetic acid and eating behavior in bulimia nervosa.

Topics: Adult; Bulimia; Depressive Disorder; Female; Humans; Monoamine Oxidase Inhibitors; Phenylacetates; Piperidines; Placebos; Psychiatric Status Rating Scales; Severity of Illness Index; Single-Blind Method

A low dose of cisapride (5 mg b.i.d.) produced rapid relief from nausea elicited by the initiation of treatment with a selective serotonin reuptake inhibitor in eight patients. This effect of cisapride is presumably related to its serotonin3 antagonistic property.

Topics: Adult; Cisapride; Depressive Disorder; Drug Therapy, Combination; Female; Humans; Male; Nausea; Piperidines; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists

Topics: Acute Disease; Cyproheptadine; Depressive Disorder; Drug Interactions; Female; Fluoxetine; Humans; Middle Aged; Monoamine Oxidase Inhibitors; Paranoid Disorders; Piperidines; Recurrence

We have examined the effects of two monoamine oxidase (MAO) inhibitors with different mechanisms of action--phenelzine and brofaromine--on peripheral serotonergic (5-hydroxytryptamine [5-HT]) measures, sensitive to the inhibition of MAO-A (intra- and extracellular 5-HT and related metabolites in blood). Both drugs increased the concentration of 5-HT in platelet-free plasma (254%, p less than 0.001) in patients with depressive illness (DSM-III-R) after 6 weeks of daily treatment. Platelet 5-HT was also increased significantly in both drug treatment groups but more marked in the patient group treated with phenelzine. The acid/amine ratio at 6 weeks was 30% of pretreatment values (p less than 0.000) and individual variability correlated significantly with the Hamilton Rating Scale for Depression. Plasma 5-HT increased more markedly in responders than in nonresponders and a significant inverse relationship surfaced between plasma 5-HT and the Hamilton Rating Scale for Depression. The results support other reports of comparable antidepressant efficacy for brofaromine and phenelzine, both inhibitors of MAO-A in humans. The consistent relationship we found between the biochemical and clinical changes again suggests and supports a key role of 5-HT in the antidepressant effect of these MAO inhibitors.

Topics: Adult; Ambulatory Care; Depressive Disorder; Female; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Monoamine Oxidase Inhibitors; Phenelzine; Piperidines; Serotonin; Treatment Outcome

In vitro receptor-binding profiles and in vivo pharmacological studies have shown risperidone to be a potent mixed serotonin-S2 dopamine-D2-like receptor antagonist. While anti-D2 activity may relate to the antipsychotic potency of neuroleptic drugs, an antidepressive efficacy of substances with anti-S2 activity has been suggested. In an open pilot-study, ten patients with schizodepressive disorders or a DSM-III-R diagnosis of psychotic major depressive episodes were treated with risperidone (2-10 mg/d) for six weeks. Weekly psychopathological evaluation was performed, including BPRS, SANS, SAPS, VAS scales, and AIMS and UKU for the assessment of side-effects. Generally, the psychotic syndrome (BPRS, SANS and SAPS) decreased markedly in all patients; seven patients also showed a clinically significant improvement of depressive symptoms (BPRS). Except for two patients who needed biperiden because of extrapyramidal side-effects, the tolerance of risperidone was good. The antipsychotic and antidepressive properties of risperidone shown in our pilot study are promising enough to merit full double-blind controlled trials for further evaluation of its therapeutic value in this broad spectrum of psychiatric disorders.

Topics: Adult; Aged; Antipsychotic Agents; Depressive Disorder; Female; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Syndrome

Topics: Benzamides; Depressive Disorder; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Piperidines

Topics: Antidepressive Agents, Tricyclic; Depressive Disorder; Humans; Incidence; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Seizures; Serotonin; Suicide

The tolerability and antidepressive effect of brofaromine, a selective MAO-A inhibitor was tested in 14 depressive patients. None of the patients showed blood pressure or pulse frequency changes after ingesting tyramine-enriched meals. Four instances of agitation were observed as side effects. In two of these cases, the appearance of paranoid thinking and suicidal tendencies led to premature termination of the study. In 3 cases sleep disturbances, in particular difficulties in falling asleep, were observed. In the test of antidepressive effectiveness (measured on the HAMD-scale) significant improvement was observed from day 14 onwards.

Topics: Adult; Aged; Blood Pressure; Depressive Disorder; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales; Pulse

Five patients who reacted with the hypersensitive syndrome to zimeldine showed no reaction to one of two other selective 5-HT reuptake inhibitors, citalopram or paroxetine. This further strengthens the impression that the mechanism for the hypersensitivity syndrome induced by zimeldine does not seem to be related primarily to the 5-HT reuptake inhibition as such.

Topics: Aged; Aged, 80 and over; Antidepressive Agents; Citalopram; Combined Modality Therapy; Depressive Disorder; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Liver Function Tests; Male; Paroxetine; Piperidines; Serotonin Antagonists; Zimeldine

Topics: 1-Naphthylamine; Antidepressive Agents; Depressive Disorder; Humans; Paroxetine; Piperidines; Sertraline

The serotonin transporter labeled in platelets by 3H-imipramine or 3H-paroxetine binding has been suggested to be a peripheral marker for changes in serotonin uptake in the brain that may be related to depression. The present study was designed to determine whether major changes in central serotonergic innervation modify the platelet serotonin transporter as labeled by 3H-paroxetine binding. Fifteen days after the intracerebroventricular administration of 5,7-dihydroxytryptamine (250 micrograms/animal) to rats to lesion central serotonergic neurons, serotonergic innervation was reduced by 82% in the cortex and 98% in the hippocampus as determined by endogenous serotonin levels. The maximum binding of 3H-paroxetine was reduced by 55% in the cortex and was undetectable in the hippocampus. Serotonin levels and 3H-paroxetine binding in platelets were not, however, significantly modified in the same animals. Thus, following a major serotonergic lesion in the brain, changes in the platelet serotonin transporter do not parallel serotonergic changes in the brain. The hypothesis that binding to the platelet serotonin transporter is a state-dependent marker of brain serotonergic activity therefore appears to be unlikely.

Topics: 5,7-Dihydroxytryptamine; Animals; Brain; Depressive Disorder; Imipramine; Male; Paroxetine; Piperidines; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists

Topics: Depressive Disorder; Drug Therapy, Combination; Humans; Lithium; Maprotiline; Monoamine Oxidase Inhibitors; Pilot Projects; Piperidines; Psychiatric Status Rating Scales

In an open clinical trial 13 depressives significantly improved under the reversible and selective type-A monoamine oxidase (MAO) inhibitor brofaromine. The inhibitory potency of deproteinated plasma on a crude MAO preparation from human placenta was measured as a parameter for plasma brofaromine. There were no significant differences in plasma MAO inhibitory potency between responders (improvement greater than 50%; n = 5) and non-responders. MAO inhibitory potency significantly (p less than 0.05) increased parallel to the increase of the dosage from 50 mg b.i.d. to t.i.d. confirming the validity of this technique. The biologic assay, however, overestimated brofaromine by a factor of two in acute kinetic experiments with healthy volunteers as compared to a chromatographic technique, although both methods significantly correlated (r = 0.928).

Topics: Adult; Aged; Chromatography, Liquid; Depressive Disorder; Female; Humans; In Vitro Techniques; Male; Middle Aged; Mitochondria; Monoamine Oxidase Inhibitors; Piperidines; Placenta; Pregnancy

The effect of pretreatment with ritanserin, a potent and selective serotonin-S2 (5-HT2) receptor antagonist, on the prolactin (PRL) response to electroconvulsive therapy (ECT) was studied in seven female patients suffering from major depressive disorder. They were given either ECT alone, or ECT after 10 or 20 mg ritanserin PO, and PRL was estimated in blood samples taken at times -5, 0, +5, +15, +30 and +60 min. The PRL responses after drug administration were not different from the responses after ECT alone. We conclude that, if serotonergic mechanisms are involved in the ECT-induced PRL increase, this neuroendocrine response seems to be rather a 5-HT1 than 5-HT2 receptor mediated event.

Topics: Aged; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Middle Aged; Piperidines; Prolactin; Ritanserin; Serotonin Antagonists

Topics: Adult; Brain; Brain Mapping; Depressive Disorder; Dominance, Cerebral; Female; Frontal Lobe; Humans; Male; Middle Aged; Paroxetine; Piperidines; Putamen; Receptors, Serotonin; Retrospective Studies; Serotonin Antagonists; Substantia Nigra; Suicide

Brain serotonin (5-HT) uptake sites were quantitated, by saturation binding of [3H]paroxetine, in 10 brain regions from 22 suicide victims and 20 control subjects. Suicide victims were restricted to those subjects in whom a firm retrospective diagnosis of depression was established and who had not recently been prescribed antidepressant drugs. The Kd and Bmax of [3H]paroxetine did not differ significantly between controls and depressed suicides in any of the brain regions. In putamen, Bmax values of suicides who died non-violently were lower than controls, whereas those who died by violent methods did not differ from controls. No significant differences between violent or non-violent suicides and their matched controls were found in other brain areas. These results offer little support for the view that suicide/depression is associated with an abnormality in 5-HT uptake.

Topics: Brain Chemistry; Depressive Disorder; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Receptors, Serotonin; Retrospective Studies; Serotonin Antagonists; Suicide; Tritium

In the treatment of depression, when antidepressant drug choice is made according to alterations of erythrocyte membrane transport of L-tyrosine and L-tryptophan in the individual patient, the clinical results are superior to those obtained when drugs are prescribed according to the physician's judgment. This is demonstrated by comparing three experimental groups: I, 100 patients treated in relation to their L-tyrosine and L-tryptophan transport; II, 30 patients treated according to the clinician's experience; III, 38 subjects treated against the L-tyrosine and L-tryptophan transport indications. In these groups, the frequency of patients improved by more than 70% is 77%, 47%, and 16%, respectively.

Topics: Adult; Aged; Antidepressive Agents; Depressive Disorder; Erythrocyte Membrane; Female; Fluvoxamine; Humans; Imipramine; Male; Mianserin; Middle Aged; Monoamine Oxidase Inhibitors; Oximes; Piperidines; Receptors, Adrenergic; Receptors, Serotonin; Tryptophan; Tyrosine

Human platelet membranes were incubated with 3H-imipramine, 3H-paroxetine or 3H-chlorimipramine. It was found that chlorimipramine remained in the membranes, as it was impossible to remove this antidepressant drug by normal washing procedures. Similar results, although to a lesser degree, were found with paroxetine, whereas imipramine could be washed away from the membranes. Treatment of volunteers with chlorimipramine strongly reduced platelet imipramine binding probably due to the presence of chlorimipramine in the membranes during the binding assay. These results suggest that the low imipramine binding reported in depressed patients, at least in some cases, may have been caused by antidepressant drugs or drug metabolites remaining in the platelet membrane preparations.

Topics: Antidepressive Agents; Blood Platelets; Carrier Proteins; Cell Membrane; Clomipramine; Depressive Disorder; Humans; Imipramine; Paroxetine; Piperidines; Receptors, Drug; Receptors, Neurotransmitter; Serotonin Antagonists

In an open clinical trial, 13 depressives were treated with the reversible and selective type-A monoamine oxidase (MAO)-inhibitor brofaromine (CGP 11 305 A), the inhibitory potency of deproteinated plasma on a crude MAO preparation from human placenta was measured as a parameter for plasma brofaromine and possibly active metabolites of brofaromine. Patients significantly (p less than 0.01) improved under brofaromine. There were, however, no significant differences in plasma MAO-inhibitory potency between responders (improvement greater than 50%; n = 5) and nonresponders and no correlations with the change from baseline of the total Hamilton Depression Score (HAMD) or with changes of sleep (change from baseline of the HAMD sleep items). MAO-inhibitory potency significantly (p less than 0.05) increased parallel to the increase of the dosage from 50 mg b.i.d. to t.i.d., confirming the validity of this technique. The biological assay applied is a simple and reliable alternative when estimating the plasma concentrations of brofaromine and, possibly, other reversible MAO inhibitors.

Topics: Adult; Aged; Depressive Disorder; Female; Humans; Male; Middle Aged; Mitochondria; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Placenta; Psychiatric Status Rating Scales

Topics: Antidepressive Agents; Depressive Disorder; Humans; Paroxetine; Piperidines; Serotonin Antagonists

Topics: Amitriptyline; Antidepressive Agents; Depressive Disorder; Electromyography; Humans; Neural Conduction; Paroxetine; Peripheral Nerves; Piperidines; Serotonin Antagonists

Topics: Antidepressive Agents; Depressive Disorder; Humans; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Retrospective Studies; Serotonin Antagonists

Topics: Adult; Brain; Depressive Disorder; Female; Humans; In Vitro Techniques; Male; Paroxetine; Piperidines; Receptors, Serotonin; Serotonin Antagonists; Suicide

Studies using 3H-imipramine binding in platelets as a means of exploring the serotonin transport system in depressed patients have produced inconsistent findings. For this reason, we studied 3H-paroxetine binding in platelets, because we believed it might provide a more reliable ligand for studying serotonin transport. Subjects were 23 depressive inpatients and 23 normal controls. No differences in the maximal number of binding sites (Bmax) or in the dissociation constant (Kd) were found between depressives and controls.

Topics: Adult; Antidepressive Agents; Blood Platelets; Depressive Disorder; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Psychological Tests; Serotonin

Topics: Adult; Aged; Antidepressive Agents; Depressive Disorder; Drug Evaluation; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Psychiatric Status Rating Scales

In our open study, ritanserin was shown to be an antidepressant low in side effects with a rapid onset of action. In contrast to the results reported by Ceulemanns, patients suffering from melancholia could also be treated with ritanserin. Similar to amitriptyline, ritanserin is able to provoke psychotic symptoms in schizophrenic patients despite the absence of an anticholinergic action. Ritanserin appears to improve mood and subjective well-being of depressive schizophrenic patients as supplementary therapy to a highly potent neuroleptic. This is consistent with the experience of Gelders. The relevance of the results described is restricted by the fact that the patients received an above-average intensive medical care besides the pharmacotherapy. In addition, the expectations of the patients with regard to ritanserin were extremely high and they expected an above-average effect of the ritanserin treatment.

Topics: Adult; Depressive Disorder; Female; Humans; Male; Mental Disorders; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Ritanserin; Serotonin Antagonists

[3H]-Imipramine and [3H]-paroxetine label with high affinity a site which is associated with the serotonergic transporter in brain and platelets. The pharmacological profile of inhibition by drugs of [3H]-imipramine and [3H]-paroxetine binding is highly correlated with the potency of the drugs to inhibit the uptake of 5HT. Denervation of serotonergic neurons by electrolytic lesions or with 5,7-dihydroxytryptamine produces marked decreases in the density of [3H]-imipramine as well as [3H]-paroxetine binding. Dissociation kinetic experiments support the view that the substrate recognition site for 5HT is different from the modulatory site which is labelled by [3H]-imipramine or [3H]-paroxetine. The existence of an endogenous ligand acting on the [3H]-imipramine recognition site to modulate the 5HT transporter was proposed by several laboratories. [3H]-Imipramine binding in platelets appears to be a biological marker in depression. Studies carried out in several laboratories report a significant decrease in the Bmax of platelet [3H]-imipramine binding without changes in Kd, when severely depressed untreated patients are compared with healthy volunteers matched for age and sex. The Bmax of platelet [3H]-imipramine binding appears to be a state-dependent biological marker in depression. It is tempting to speculate that the endocoid of the [3H]-imipramine recognition site may play a role in the pathogenesis of depression.

Topics: Animals; Antidepressive Agents; Blood Platelets; Brain Chemistry; Carrier Proteins; Depressive Disorder; Female; Humans; Imipramine; Male; Paroxetine; Piperidines; Rabbits; Rats; Receptors, Drug; Receptors, Neurotransmitter; Receptors, Serotonin; Serotonin

In an open clinical trial the authors treated 18 hospitalized patients suffering from endogenous depression with brofaromine (CGP 11305A), a competitive, selective, and short-acting inhibitor of type A monoamine oxidase (MAO). Four patients were defined as good responders, as they had a final HAMD score of between 0 and 7 points. Four patients were judged as improved, with final HAMD scores of between 8 and 15 points, while the remaining eight patients failed to respond (final HAMD score greater than or equal to 16 points). The major observations were a beneficial influence on drive in most patients, while paranoid symptoms worsened markedly, rendering the substance contraindicated in psychotic depression. Brofaromine appears to be safe and well tolerated and largely free of side effects. As objectified by the tyramine pressor test, dietary restrictions during brofaromine treatment require less stringency than is the case with conventional MAO inhibitors. The specificity of brofaromine to inhibit deamination is limited to MAO-A, since no reduction in platelet MAO activity was measurable. Sleep EEG recordings in a subset of patients reveals that the amount of rapid eye movement (REM) sleep is significantly reduced during brofaromine treatment.

Topics: Adult; Aged; Blood Platelets; Depressive Disorder; Dexamethasone; Electroencephalography; Female; Humans; Male; Middle Aged; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Personality Assessment; Piperidines; Serotonin; Sleep, REM; Tyramine

The similarity between the metabolic pathways of serotonin in platelets and serotoninergic nerve endings has often been emphasized. The turnover of serotonin was therefore investigated in two diseases: hypertension (as central serotoninergic neurones appear to modulate central sympathetic nervous activity) and depression (as a central 5-HT-deficiency and a low 3H-imipramine binding on platelets have been described in patients with endogenous depression). Mean platelet 5-HT level was significantly lower in essential hypertensives than in controls. A reduction in platelet 5-HT level was also observed in depression and was more marked in women than in men. Serotonin level was only weakly related to the severity of the diseases. In some hypertensive patients, administration of ketanserin resulted in a reduction of blood pressure without affecting 5-HT level. In depressive patients, maprotiline and chlorimipramine acted differently on 5-HT level but both improved the clinical symptoms.

Topics: Adult; Antidepressive Agents; Blood Platelets; Depressive Disorder; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Serotonin; Serotonin Antagonists; Sex Factors

Dihydroxy-phenyl-ethylene-glycol (DOPEG or DHPG), a deaminated catabolite of noradrenaline formed after presynaptic re-uptake, is a good marker of metabolic activity in noradrenergic pathways. Plasma levels of free, conjugated and total DOPEG were measured by a radioenzymatic method in 45 patients with major depression selected according to the DSM 3 criteria and in 45 matched controls. A significant decrease in man DOPEG levels was observed in all depressive patients. A dexamethasone suppression test performed in these patients showed no difference in DOPEG levels between responders and non-responders, thus failing to support the hypothesis that subjects with low noradrenergic drive escape suppression. There was no correlation between plasma DOPEG levels and urinary excretion of methoxy-hydroxy-phenylglycol (MOPEG), another marker of noradrenaline metabolic activity. Thirty-one patients were treated with a specific monoaminergic antidepressant: maprotiline or indalpine; contrary to urinary MOPEG levels, plasma DOPEG levels had no predictive value concerning the response to this category of antidepressants. The various possible reasons for the fall in DOPEG observed in depressive patients are discussed.

Topics: Adult; Antidepressive Agents; Brain; Depressive Disorder; Dexamethasone; Female; Glycols; Humans; Male; Maprotiline; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Piperidines

Topics: Adult; Aged; Antidepressive Agents; Antidepressive Agents, Tricyclic; Depressive Disorder; Depressive Disorder, Major; Dibenzocycloheptenes; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperidines

Topics: Brain; Depressive Disorder; Dexamethasone; Glycols; Humans; Hypothalamo-Hypophyseal System; Maprotiline; Methoxyhydroxyphenylglycol; Norepinephrine; Piperidines; Pituitary-Adrenal System; Random Allocation

In patients with Alzheimer-type dementia, in addition to the well-known losses of cholinergic neurones, there is evidence of degeneration of the noradrenergic and serotonergic innervation of the cerebral cortex. While noradrenergic and cholinergic receptors are preserved there is a loss of serotonin S1 and S2 receptors, particularly in the temporal lobe. The loss of serotonin S2 receptors may occur at an early stage of the disease and, in temporal and frontal cortex, is correlated with the loss of somatostatin immunoreactivity. In patients dying in hospital with depression, and in individuals committing suicide, there are no consistent changes in monoamine metabolites. Noradrenergic, serotonergic, and other neurotransmitter receptors were found to be unchanged, although there was a moderate decrease in imipramine binding in a small group (n = 6) of subjects with a history of depression, who had committed suicide.

Topics: Aged; Aging; Alzheimer Disease; Binding, Competitive; Biogenic Amines; Brain; Choline O-Acetyltransferase; Depressive Disorder; Female; Humans; Hydroxyindoleacetic Acid; Ketanserin; Male; Middle Aged; Piperidines; Radioligand Assay; Receptors, Neurotransmitter; Receptors, Serotonin; Serotonin; Sex Factors; Suicide

Paroxetine, a new, potent and selective serotonin (5-HT) uptake inhibitor has been evaluated in an open study for its clinical effect as well as its effect on the 5-HT concentration in whole blood in 19 patients with depressive illness. Paroxetine was administered in daily doses of 20 to 60 mg. The global evaluation after six to eight weeks showed a marked improvement in 11 patients, a moderate improvement in four and no change in four patients. Assessment with the Hamilton Rating Scale for Depression in ten patients showed a reduction from a mean score of 22.7 to 6.6 in six weeks. Maximal reduction was, however, first seen in three of the patients after 8 to 12 weeks. No correlation between the antidepressant effect and plasma concentrations of paroxetine was found. The only side effects noted with paroxetine were that two patients complained of dry mouth in the beginning of the treatment and a further patient experienced a burning sensation together with periodical light headache. Generally laboratory examinations did not show any trend towards pathological values except in one patient, where a moderate leucopenia was observed. Crista puncture/biopsy showed, however, no specific bone marrow reaction. The 5-HT concentration in whole blood was reduced to about 0.02 micrograms/ml indicating a total depletion of 5-HT from the thrombocytes. The present study indicates that paroxetine possesses a good antidepressive effect in combination with a very low frequency of side effects.

Topics: Adult; Aged; Depressive Disorder; Drug Evaluation; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Serotonin

The proserotoninergic hypothesis of depression has been for a long time founded on biochemical parameters (brain from suicide patients, CSF and plasma from depressed patients) or more recently on measurement of platelets 5-HT uptake or imipramine binding. New specific proserotoninergic agents confirm this hypothesis since indalpine, a specific 5-HT uptake inhibitor, has a neurochemical and pharmacological profile characteristics of proserotoninergic agents and is effectively antidepressant in human. 5-HT uptake inhibition seems an important property because when we compared two isomers one, a 5-HT uptake inhibitor and at the same time 5-HT releaser, and the other only releaser, we observed that the first has experimental properties similar to indalpine whereas the second has not the classical spectrum of a proserotoninergic agent.

Topics: Animals; Brain; Depressive Disorder; Dopamine; Humans; Norepinephrine; Piperidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Synaptic Transmission

In an open study the cholinolytic biperiden was administered to 10 severely depressed inpatients in an average dose of 12 mg per day for 30 days. Patients were classified according to the International Classification of Diseases, the research Diagnostic Criteria and the Newcastle Scale. A significant improvement was demonstrated in the global score of the Hamilton Depression Scale (p less than 0.001). Especially the factors retardation (p less than 0.001) and agitation (p less than 0.001) and the items depressed mood (p less than 0.001), initial insomnia (p less than 0.05), work and interest (p less than 0.001) and gastrointestinal symptoms (p less than 0.001) could favorably be influenced. Nevertheless, biperiden treatment had to be discontinued after three weeks in two patients because of a paranoid syndrome in one case and symptoms of inner restlessness and disturbances of vital feelings in the other case. There was a positive correlation between the clinical response and the cortisol non-suppressability to dexamethasone prior to the study (p less than 0.03). These results taken together with other findings from the literature suggest that cholinergic mechanisms may have an important impact on the pathogenesis of certain forms of depression.

Topics: Adult; Aged; Biperiden; Depressive Disorder; Dexamethasone; Electroencephalography; Female; Humans; Male; Middle Aged; Parasympathetic Nervous System; Piperidines; Psychiatric Status Rating Scales

Topics: Amitriptyline; Amphetamine; Amphetamines; Barbiturates; Benactyzine; Chlordiazepoxide; Deanol; Depression; Depressive Disorder; Diagnosis; Diazepam; Drug Therapy; Geriatrics; Humans; Imipramine; Meprobamate; Methylphenidate; Monoamine Oxidase Inhibitors; Phenmetrazine; Piperidines; Psychotherapy; Toxicology

Topics: Atropine; Coma; Depression; Depressive Disorder; Drug Combinations; Glycolates; Hallucinogens; Humans; Piperidines; Pyrrolidines

Topics: Basal Metabolism; Depression; Depressive Disorder; Piperidines

Topics: Central Nervous System Stimulants; Depression; Depressive Disorder; Disorders of Excessive Somnolence; Fatigue; Piperidines

Topics: Depression; Depressive Disorder; Piperidines

Topics: Aged; Depression; Depressive Disorder; Fatigue; Humans; Patients; Piperidines

Topics: Central Nervous System Stimulants; Depression; Depressive Disorder; Female; Genital Diseases, Female; Gynecology; Humans; Obstetrics; Piperidines

Topics: Depression; Depressive Disorder; Piperidines

Topics: Depression; Depressive Disorder; Piperidines

Topics: Central Nervous System Stimulants; Depression; Depressive Disorder; Mental Disorders; Methylphenidate; Piperidines; Psychotherapy; Reserpine; Secologanin Tryptamine Alkaloids

Topics: Central Nervous System Stimulants; Depression; Depressive Disorder; Humans; Piperidines

Topics: Central Nervous System Agents; Central Nervous System Stimulants; Depression; Depressive Disorder; Electroconvulsive Therapy; Methylphenidate; Nervous System; Orthotic Devices; Piperidines