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PubMed2002

A neurochemically distinct dorsal raphe-limbic circuit with a potential role in affective disorders.

The serotonergic system arising from the dorsal raphe nucleus (DR) has long been implicated in psychiatric disorders, and is considered one site of action of classical anxiolytic and antidepressant agents. Recent studies implicate the DR as a site of action of novel anxiolytic and antidepressant agents that target neuropeptide systems, such as corticotropin-releasing factor (CRF) and neurokinin 1 (NK1) antagonists. The present study identified unique characteristics of the dorsomedial DR that implicate this particular subregion as a key component of a circuit, which may be targeted by these diverse psychotherapeutic agents. First, it was observed that a cluster of CRF-containing cell bodies was present in the dorsomedial DR of colchicine-treated rats. Dual-labeling immunohistochemistry revealed that almost all CRF-containing neurons were serotonergic, implicating CRF as a cotransmitter with serotonin in this subpopulation of DR neurons. Moreover, dendrites laden with immunoreactivity for NK1 had a striking topographic distribution surrounding and extending into the dorsomedial subregion of the DR, suggesting that NK1 receptor ligands may selectively impact the dorsomedial DR. Finally, anterograde tract tracing from the dorsomedial DR combined with CRF immunohistochemistry revealed that CRF-containing axons from this subregion project to CRF-containing neurons of the central nucleus of the amygdala. Taken together, the present results reveal a circuit whereby NK1 receptor activation in the dorsomedial DR can impact on limbic sources of CRF that have been implicated in emotional responses. This circuit may be relevant for understanding the mechanism of action of novel psychotherapeutic agents that act through NK1 or CRF receptors.

Animals↗

PubMed1998

Double-blind study of the efficacy and safety of milnacipran and imipramine in elderly patients with major depressive episode.

The novel antidepressant agent milnacipran is a dual and equipotent serotonin and noradrenaline reuptake inhibitor. The aim of this double-blind study was to compare the efficacy and safety of milnacipran (50 mg twice daily) with that of imipramine (50 mg twice daily) in elderly patients with major depressive episode. A total of 219 patients were randomly assigned to 8 weeks of double-blind treatment with either milnacipran or imipramine; 72 patients withdrew from the study. At the end of treatment no significant differences were found between milnacipran and imipramine in antidepressant efficacy. A significantly greater number of side-effects, particularly anticholinergic effects, was observed in the imipramine group. Milnacipran may be preferable to imipramine in elderly depressed patients, as it provides the same antidepressant activity as imipramine with a lower incidence of side-effects, and does not impair cognitive ability.

Adrenergic Uptake Inhibitors↗

PubMedDate not supplied

Kleptomania after head trauma: two case reports and combination treatment strategies.

The purpose of this paper is to add to the growing number of reports about kleptomania occurring in relation to brain injury as well as to present the authors' findings regarding treatment strategies. The authors present two case reports of patients who developed the new onset of kleptomania after closed head trauma. Both patients had comorbid psychiatric symptoms associated with the kleptomania. Antidepressant monotherapy was not beneficial in reducing kleptomania in either patient. Kleptomanic behavior was successfully treated in both patients, however, through combination treatment using an antidepressant agent together with adjunctive cognitive behavioral therapy or adjunctive naltrexone. In one patient, single photon emission tomography showed a perfusion deficit in the left temporal lobe. Various hypotheses regarding this finding and the etiopathology of kleptomania are discussed. Review of current work in the field suggests that kleptomania is a heterogeneous disorder that shares features of both impulse and addiction disorders as well as affective spectrum disorders.

Adult↗

PubMed1995

A double-blind, randomized study to provide safety information on switching fluoxetine-treated patients to paroxetine without an intervening washout period.

BACKGROUND: The long elimination half-lives of fluoxetine and norfluoxetine, the active metabolite of fluoxetine, are of potential consequence when alternative antidepressant agents are introduced after the termination of fluoxetine therapy. It is not known whether paroxetine, an antidepressant agent in the same pharmacologic class as fluoxetine, can be substituted for fluoxetine without the need for an intervening washout period. The objective of this trial was to assess the tolerability of an immediate switch from fluoxetine to paroxetine therapy. METHOD: Patients who were treated for moderate to moderately severe major depressive disorder (DSM-III-R 296.2 or 296.3) with a stable dose of fluoxetine for a minimum of 6 weeks' duration were randomized in a double-blind fashion to one of two treatment groups. One group (N = 123) was started on 20 mg of paroxetine daily the morning after their last dose of fluoxetine, and the other group (N = 119) was started on 20 mg of paroxetine daily following a 2-week placebo-washout period. Patient visits were scheduled at weekly intervals for a total of 4 weeks. Adverse experience monitoring was conducted at each visit. RESULTS: There was no difference in the proportion of patients who discontinued prematurely from the trial due to an adverse experience. Eight patients in the immediate-switch group and 6 patients in the placebo-washout group withdrew from the trial in response to an adverse experience (p = .63, chi-square). The overall profile of adverse experiences was similar in the two treatment groups over the 4-week period. The incidence of adverse experiences in the first 2 weeks following the initiation of paroxetine was generally lower in the group with the intervening 2-week placebo-washout period. CONCLUSION: The immediate switch from fluoxetine to paroxetine was as well tolerated as the switch to paroxetine after a 2-week placebo-washout period.

Adult↗

PubMed1980

[Metabolism and blood levels study of antidepressants: a rationale of their therapeutical use (author's transl)].

The authors show with some examples the interest of pharmacokinetics for the optimization of the therapeutical use of antidepressive agents. They give some indications about bioavailabilty, metabolism and half-life of these compounds and note the importance of the individual variations. They also analyze the studies on the possible relations between the clinical response and the steady-state plasma levels of the unchanged drug and/or its active metabolite. The relation between these two parameters would be linear for imipramine, amitriptyline, clomipramine, doxepine, dibenzepine, and curvilinear for nortriptyline, desipramine, protriptyline, maprotiline and mianserine, especially in endogenous depression. From a previous pharmacokinetic study calculations allow to predict the steady-state plasma concentrations. The question of the side effects and drug interactions is considered.

Antidepressive Agents↗

PubMed1988

Comparison of desipramine, amitriptyline, zimeldine and alaproclate in six animal models used to investigate antidepressant drugs.

In the present paper the acute actions primarily of the tricyclic antidepressants amitriptyline and desipramine, the atypical antidepressant zimeldine and the potential antidepressant alaproclate were evaluated in six models used for studying antidepressant agents. These included the forced swim test, a modified learned helplessness procedure, the clonidine hypothermia test, the social dominance test (using the interaction with clonidine), a differential-reinforcement-of-low-rates (DRL-72s) schedule and conditioned avoidance response. The results showed desipramine to be effective in all the tests employed. Zimeldine was effective in the learned helplessness, DRL-72s and domination tests, but also caused notable deficits in two-way active avoidance response. Alaproclate was effective in all the tests except the domination paradigm. Amitriptyline was effective in all tests employed. The results are discussed in relation to the possible mechanism of action of these compounds in the test models employed.

Alanine↗

PubMed1996

Pharmacological validation of the chronic mild stress model of depression.

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions, and this effect was reversed by chronic treatment with a variety of antidepressant drugs. The present study reports three experiments examining the effects in this model of further antidepressant agents, a number of non-antidepressants, and some compounds of indeterminate clinical status. Male Wistar rats were exposed sequentially to a variety of mild stressors, which continued throught the experiments. Drug treatments commenced after 3 weeks of stress, by which time intake of a 1% sucrose solution (measured in a 1-h weekly test) was significantly depressed. No drug effects were seen after 1 week of treatment. Normal levels of sucrose drinking were seen following chronic (3-5 weeks) of treatment with the antidepressants imipramine (10 mg/kg per day), brofaromine (20 mg/kg per day), and buspirone (5 mg/kg per day). Positive effects were also seen following chronic treatment with atropine (1 mg/kg per day) and mepyramine (5 mg/kg per day). d-Amphetamine (1 and 3 mg/kg per day), the neuroleptics haloperidol and chlorprothixene (1 mg/kg per day), and morphine (administered at doses rising to 110 mg/kg per day) were ineffective; amphetamine (3 mg/kg) and morphine decreased sucrose intake in control animals. No inferences can be drawn from the effects of atropine and mepyramine, which are of indeterminate clinical status; data from the other seven agents tested support the hypothesis that the chronic mild stress model responds appropriately to antidepressant and non-antidepressant agents.

Animals↗

PubMed1994

Withdrawal phenomena associated with antidepressant and antipsychotic agents.

The withdrawal of heterocyclic antidepressants and antipsychotic agents can produce nausea, emesis, anorexia, diarrhoea, rhinorrhoea, diaphoresis, myalgias, paraesthesias, anxiety, agitation, restlessness and insomnia. The withdrawal of monoamine oxidase (MAO) inhibitors may result in severe anxiety, agitation, pressured speech, sleeplessness or drowsiness, hallucinations, cognitive impairment, delirium, suicidality and delusions of persecution. The withdrawal of antipsychotic agents may give rise to symptoms preceding the onset of psychosis. These potential harbingers of relapse include anxiety, agitation, restlessness and insomnia. The withdrawal phenomena reviewed are usually prevented by gradually reducing the total daily dosage of the pertinent drug. Antimuscarinic agents often alleviate the distress produced by the withdrawal of tricyclic antidepressants and antipsychotic agents. MAO inhibitor withdrawal syndromes may constitute medical emergencies. The prevention of the evolution of a MAO inhibitor withdrawal-precipitated syndrome is a high priority.

Adult↗

PubMed1985

Efficacy of trazodone in narcolepsy.

A 25-year-old man with narcolepsy and cataplexy experienced partial relief of symptomatology following administration of methylphenidate. Moreover, the latter caused extreme agitation and aggression. However, administration of the antidepressant agent trazodone resulted in almost complete alleviation of the narcoleptic and cataplectic attacks within 48 h after initiation of therapy. Trazodone, a novel antidepressant agent may be useful in the long-term management of individuals suffering from narcolepsy.

Adult↗

PubMed1996

Synaptic effects of antidepressants.

Catecholamines, especially norepinephrine (NE) and serotonin (5-hydroxytryptamine [5-HT]), have been implicated in the pathophysiology of depression. However, their exact roles and their interrelationship are not completely understood. Antidepressants have various effects on the body, including action at the neuronal synapses of the brain; the two most important of these effects are blockade of the reuptake of neurotransmitters, including NE, 5-HT, and dopamine, and blockade of certain neurotransmitter receptors. Currently available antidepressants may be classified as inhibitors of monoamine oxidase or as blockers of biogenic amine neurotransmitter reuptake, the latter best describing tricyclic antidepressants and selective 5-HT-reuptake inhibitors, because they block the reuptake of one or more neurotransmitters. However, recently introduced antidepressants, such as the 5-HT-NE-reuptake inhibitors, have synaptic effects that differ from those of older compounds. These synaptic effects are important in explaining certain side effects and drug-drug interactions associated with all classes of antidepresants. This article reviews the synaptic effects of marketed antidepressant agents to elucidate the anticipated side effects and drug-interaction potential of these agents.

Animals↗

PubMed2001

Pharmacological treatment of depression in older primary care patients: the PROSPECT algorithm.

PROSPECT (Prevention of Suicide in Primary care Elderly-Collaborative Trial) is testing whether a trained clinician (the 'health specialist') can work in close collaboration with a primary care physician to implement a comprehensive depression management program and improve outcomes in older depressed patients. An algorithm guiding the selection and use of antidepressant medications has been developed to assist PROSPECT health specialists. This algorithm is presented and the rationale underlying the proposed treatment sequence is discussed. The PROSPECT algorithm builds upon existing guidelines after updating them and adapting them to the special circumstances of older primary care patients. Special attention has been paid to the tolerability and the target doses of the recommended antidepressant agents and to the duration of antidepressant trials. Patients who are unable to tolerate or do not respond to an antidepressant can be switched to another agent or be treated with interpersonal psychotherapy. Agents that produce only a partial response can be combined with other antidepressants or with interpersonal psychotherapy. Treatments for which empirical evidence exists are favored. However, treatments that are often poorly tolerated by elderly patients are given lower priority than treatments more likely to be tolerated. Similarly, trials that are simpler to implement in primary care are favored.

Aged↗

PubMed1990

Antipanic drug treatments: failure to exhibit anxiolytic-like effects on defensive burying behavior.

Although the Defensive Burying paradigm has been used as a behavioral "model" for the study of anxiety and/or antianxiety agents, the effects of chronic treatment with antidepressant agents (i.e., "antipanic" agents) have not been examined in this paradigm. The present study examined the effects of two antianxiety treatments on this behavior: 1) acute treatment (30-minute pretreatment) with the benzodiazepine anxiolytic chlordiazepoxide and 2) chronic treatment (twice daily for 7-12 weeks) with the antipanic agents imipramine (IMI), desipramine (DMI) or pargyline (PARG). Prior to testing, female Sprague-Dawley rats were placed in a 40 x 30 x 40 cm Plexiglas chamber containing clay bedding material (5 cm deep) for 30-minute periods on each of four consecutive days. On the fifth day, a wire-wrapped prod was placed at one end of the chamber. Rats were placed in the chamber individually and a 3 mA shock was delivered upon contact with the prod. Defensive Burying behavior (i.e., the moving of bedding material toward or over the prod) was recorded for 15 minutes postshock. In a dose-dependent manner, acute treatment with chlordiazepoxide reduced the frequency of occurrence of burying behavior, increased the latency to initiation of burying, and decreased the duration of burying. In contrast, chronic treatment with IMI, DMI, or PARG failed to exhibit anxiolytic-like effects on any measure of Defensive Burying. These data suggest that the Defensive Burying paradigm may not be an "animal model" for the study of panic disorder and potential antipanic agents.

Animals↗

PubMed1985

GABAergic effects of reserpine following chronic treatment.

Reserpine-induced depression has been used as an animal model to screen for antidepressant agents. Chronic (14-day) treatment with reserpine resulted in a significant increase in beta-adrenergic receptor binding in the cerebral cortex and the hippocampus, which was partially prevented by chronic treatment with either the antidepressant imipramine, the GABA-A agonist THIP or, the GABA-B agonist baclofen. Chronic treatment with reserpine also significantly increased 3H-GABA receptor binding, which was partially prevented by chronic treatment with either imipramine or THIP. Both subchronic and chronic administration of reserpine resulted in a decrease in GABA concentrations in the cerebral cortex and hippocampus. These data demonstrate the effect of reserpine treatment on the GABA-ergic system, and add further support for a functional coupling between the noradrenergic and GABA-ergic systems, which may be important for the mechanism of action of antidepressant agents.

Animals↗

PubMedDate not supplied

Hiccup and apparent myoclonus after hydrocodone: review of the opiate-related hiccup and myoclonus literature.

The author recently encountered a patient with hiccups, intermittently accompanied by apparent focal rhythmic diaphragmatic myoclonus after hydrocodone administration. Review of the literature disclosed a paucity of previous reports of hiccup, but many reports of myoclonus after opiate administration. A wide variety of opiates and routes of administration have been implicated, but high doses and the presence of other agents (antipsychotics, antiemetics, nonsteroidal antiinflammatory agents, antidepressants) may pose special risks. Review of the literature suggests three types of opiate-related myoclonus. Opiate-induced myoclonus (OIM) is often generalized and is either periodic or associated with rigidity. Opiate-induced myoclonus frequently occurs in the context of underlying medical conditions, D2 antagonist coadministration, or other drugs (nonsteroidal anti-inflammatory agents, antidepressants), and usually responds to either naloxone or benzodiazepines. Intrathecal OIM has not been linked to D2 antagonist coadministration or benzodiazepine responsiveness but may be associated with non-steroidal antiinflammatory agents. Opiate withdrawal myoclonus may be stimulus-sensitive, associated with D2 antagonist coadministration, and responsive to benzodiazepines and unresponsive to naloxone. There are several problems in interpreting the literature, and more study is needed. Opiatergic, serotonergic, dopaminergic, and other mechanisms are considered.

Analgesics, Opioid↗

PubMed1991

Citalopram. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness.

Citalopram is an antidepressant belonging to a new class of drugs which enhance serotoninergic neurotransmission through potent and selective inhibition of serotonin reuptake. Preliminary trials suggest that its short term therapeutic efficacy is significantly greater than that of placebo and mianserin, and comparable to that of amitriptyline, maprotiline and imipramine. It appears to be a weaker antidepressant agent than clomipramine, but better tolerated. Its elimination half-life of 33 hours permits once daily oral administration. Symptomatic improvement obtained with short term treatment has been maintained when therapy has been extended for up to 1 year; in the few patients studied for this extended period, the relapse rate was lower than with fluvoxamine, fluoxetine or imipramine. Compared to standard antidepressant agents, citalopram is well tolerated. It does not appear to be cardiotoxic, has not been associated with seizures in humans, and is relatively nonsedating. Unlike the tricyclic antidepressants, citalopram has minimal anticholinergic effects. Mild and transient nausea, with or without vomiting, is the most frequent adverse effect--occurring in 20% of patients--and increased perspiration, headache, dry mouth, tremor and insomnia are experienced by 15 to 18% of patients. Citalopram thus offers similar therapeutic efficacy and a more favourable tolerability profile than the tricyclic antidepressants. Preliminary data suggest that it may be particularly useful in patients who cannot tolerate the anticholinergic or cardiovascular side effects of tricyclic antidepressants and in those for whom sedation is not indicated.

Animals↗

PubMed1996

Clinical implications of antidepressant pharmacokinetics and pharmacogenetics.

OBJECTIVE: To review available data on pharmacokinetic and pharmacogenetic influences on the response to antidepressant therapy, analyze the mechanisms for and clinical significance of pharmacokinetic and pharmacogenetic differences, and explain the implications of pharmacokinetics and pharmacogenetics for patient care. DATA SOURCES: A MEDLINE search of English-language clinical studies, abstracts, and review articles on antidepressant pharmacokinetics, pharmacogenetics, and drug interactions was used to identify pertinent literature. DATA SYNTHESIS: The pharmacokinetic profiles of selected antidepressants are reviewed and the impact of hepatic microsomal enzymes on antidepressant metabolism is considered. How phenotypic differences influence the metabolism of antidepressant drug therapy is addressed. To evaluate the clinical implications of these pharmacokinetic and pharmacogenetic considerations, the findings of studies designed to elucidate drug interactions involving antidepressant agents are discussed. CONCLUSIONS: Differences in antidepressant plasma concentrations, and possibly safety, are caused by polymorphism in the genes that encode some of the cytochrome P450 isoenzymes that metabolize antidepressants. The isoenzymes 1A2, 2C9/19, 2D6, and 3A4 are the major enzymes that catalyze antidepressant metabolic reactions. Antidepressants can be either substrates or inhibitors of these enzymes, which also metabolize many other pharmacologic agents. Although the cytochrome enzymes that metabolize antidepressants have not been fully characterized, interaction profiles of the newer antidepressants are becoming more clearly defined. Determining patient phenotypes is not practical in the clinical setting, but an awareness of the possibility of genetic polymorphism in antidepressant metabolism may help explain therapeutic failure or toxicity, help predict the likelihood of drug interactions, and help clinicians better manage antidepressant drug therapy.

Antidepressive Agents↗

PubMed2001

Expanding the horizons of depression: beyond the monoamine hypothesis.

The monoamine hypothesis has dominated our understanding of depression and of pharmacological approaches to its management and it has produced several generations of antidepressant agents, ranging from the monoamine oxidase inhibitors (MAOIs), through tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs), to the recently introduced selective noradrenaline reuptake inhibitor (NARI), reboxetine. Greater receptor selectivity has improved tolerability, but not efficacy, when newer compounds are compared with the original tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors. Essentially, the newer antidepressants have the same distinguishing feature as older ones, i.e. acute enhancement of monoaminergic neurotransmission. The monoamine hypothesis cannot conclusively link the acute biochemical action of antidepressants on monoamine levels with their delayed clinical effect of 10-14 days, nor can it explain the mode of action of antidepressants that are effective despite being very weak inhibitors of monoaminergic transmission (e.g. iprindole) or, incongruously, enhancing monoamine uptake (e.g. tianeptine). Compared with other fields of medicine, there has been a lack of progress in understanding the pathophysiology of depression and producing truly novel antidepressant agents. Other biological approaches to depression, such as overactivity of the hypothalamic-pituitary-adrenal axis, hippocampal neural plasticity in response to stress, and the link between the inflammatory response and depression, offer new approaches to finding pharmacological agents, aided by improved techniques for visualising the human brain, better animal models, and increased knowledge of human markers of depression. Copyright 2001 John Wiley & Sons, Ltd.

Journal Article↗

PubMed1983

The pharmacologic treatment of schizophrenia: a progress report.

Pharmacologic agents currently used or being studied for the treatment of schizophrenia are reviewed. Neuroleptic medications are still the mainstay of treatment, but recent studies suggest new approaches to dosage and to the treatment of acute psychosis. Lithium is beneficial in psychotic illnesses with acute onset and a remitting course, regardless of the acute psychotic symptoms. Antidepressant agents may ameliorate depression in psychotic patients, but do not improve psychotic symptoms or social withdrawal. Propranolol's reported antipsychotic action has not been confirmed by controlled studies, but the drug may have a role in treating organic psychoses. The benzodiazepines, clonidine, and carbamazepine all merit more investigation as possible treatments for psychosis. The implications of differential treatment response among schizophrenic patients are discussed.

Acute Disease↗