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PubMed2005

3-(1H-pyrrol-2-yl)-2-oxazolidinones as novel monoamine oxidase type A inhibitors.

A novel series of 5-substituted-3-(1H-pyrrol-2-yl)-2-oxazolidinones 2a-s has been described as pyrrole analogues of toloxatone and befloxatone, two phenyl-oxazolidinones active as anti-MAO agents and used in antidepressant therapy. Tested against MAO-A and MAO-B enzymes, the majority of 2a-s show highly potent inhibitory effect against the A isoform of the enzyme, with Ki values in the range 0.52-0.004 microM, whilst their anti-MAO-B activity is considerably lower (Ki = >100-0.5 microM). Structurally, 2a-s differs for the substituent inserted at the C5 position of the 2-oxazolidinone ring (hydroxymethyl (2a-d), methoxymethyl (2e-h), azidomethyl (2i-l), methylaminomethyl (2m-p), and aminomethyl (2q-s)), and the size of the alkyl chain at the pyrrole N1 position (methyl, ethyl, allyl, or benzyl). As a rule, apart from the C5 substitution, the bulkier is the alkyl group at the pyrrole-N1, the lower is the anti-MAO-A activity of the compounds, being the N1-methyl derivatives 2a, 2e, 2i, and 2q among the most potent (K(iMAO-A) = 0.087-0.004 microM) and A-selective (A-selectivity ratio: >11,111-41) compounds in this series. Exceptions are represented by the N1-benzyl derivative 2d (K(iMAO-A) = 0.009 microM) and the N1-allylpyrrole 2o (K(iMAO-A) = 0.04 microM). In comparison with the reference drugs, these highly active derivatives are more potent than toloxatone, slightly less potent than befloxatone, and several times more A-selective than both the references. Such results indicate that 2a-s may represent a new promising series of antidepressant agents.

Animals↗
PubMed2001

Treatment of common mental disorders in Australian general practice.

OBJECTIVE: To determine the rates and predictors of treatments for patients with common mental disorders in Australian general practice. DESIGN AND SETTING: Cross-sectional national audit of general practices throughout Australia in 1998-1999. PARTICIPANTS: 46 515 ambulatory care patients attending 386 GPs. SCREENING TOOLS: Prevalence of common mental disorders--12 items from the 34-item SPHERE self-report questionnaire and associated classification system; pharmacological and non-pharmacological treatment provided, as reported by the GPs--questions relating to treatments provided; predictors of treatments--self-report questions about demography for patients and GPs, and about practice organisation for GPs. MAIN OUTCOME MEASURES: GPs' reported provision of pharmacological and nonpharmacological treatments; and patient, GP and practice characteristics predicting treatment provision. RESULTS: There were complete data on treatment for 39 983 patients. 27% (10752) of all patients received some form of intervention; 21% (8304) received non-pharmacological and 12% (4765) received pharmacological treatments. Non-pharmacological treatments were mostly non-specific counselling and support (83%; 6892/8304). Among the 10303 patients with the most severe level of psychological disorders, only 50% (5152) received any intervention (38% [3872] received non-pharmacological and 27% [2766] pharmacological treatments). Evidence-based treatments were provided to only 12% (4961) of all patients (and only 27% [2802] of the 10303 with the most severe disorders). Although the newer antidepressant agents were commonly prescribed, older medications (mainly tricyclic antidepressants) were prescribed to older (OR, 1.29; 95% CI, 1.07-1.56), less educated (OR, 1.41; 95% CI, 1.12-1.79) and female (OR, 1.44; 95% CI, 1.23-1.70) patients. Among the 8304 patients receiving non-pharmacological treatments, specific (evidence-based) treatments were provided to only 17% (1412); these patients were typically middle-aged (OR, 2.94; 95% CI, 2.32-3.73) and the providing GPs were typically not in full-time practice (OR, 3.34; 95% CI, 2.56-4.17). CONCLUSION: Practitioners largely provide non-specific, non-pharmacological interventions for patients with common mental disorders. Even among those with the most severe disorders, only a minority receive pharmacological or specific evidence-based non-pharmacological treatments.

Adult↗
PubMed1999

[From valium to the happy pill?].

The National Health Insurance started to refund expenditure on selective serotonin reuptake inhibitors in 1994. Questions have been raised if a significant portion of benzodiazepine users would transfer to these new drugs when they were described in the literature as also being used for light anxiety, but not carrying the addiction risk associated with benzodiazepines. The study looks at changes over a four-year period in the prescription of benzodiazepines and selective serotonin reuptake inhibitors dispensed from two pharmacies in Vest-Agder County with a total customer base of 17,800. For four years we also followed the prescription of drugs in these two groups to 1,125 patients who had been prescribed benzodiazepines in 1994. Our data show that only 5% of those receiving benzodiazepines in 1994, whom we were able to track, changed to a selective serotonin reuptake inhibitor-only therapy. 18% used a combination of the two groups of drugs and 77% continued to use benzodiazepines as before. The increase in the number of patients receiving selective serotonin reuptake inhibitors during the study period is far greater than the increase measured by number of daily doses. Selective serotonin reuptake inhibitors seem to have little influence on the use of benzodiazepines in our pharmacies' area. Our findings indicate that instead of "from Valium to Prozac" the change during the years 1994-97 can be described as "from Valium to Valium and Prozac".

Anti-Anxiety Agents↗
PubMed1977

Psychotropic drugs: mechanism of action at the neurotransmitter level.

Although the intimate mechanism by which psychotropic agents exert their therapeutic effects is still not completely clear, a large bulk of evidence supports the existence of a close correlation between their clinical antipsychotic acitivity and the ability to affect by different mechanisms brain monoamines and/or other real or putative neurotransmitters. Neuroleptic drugs of the phenothiazine type and related classes possess a blocking effect on dopaminergic transmission in nigro-striatal, mesolimbic and mesocortical areas; experiments supporting both a pre-and post-synaptic site of action have been described, together with the interference at the molecular level with DA-sensitive adenylate cyclase activity. In addition, anticholinergic activity and increase in GABA turnover in the striatum have been given as evidence to explain for some neuroleptics (e.g sulpiride, clozapine) lack of extrapyramidal side-effects. Anxiolytics seem to produce their therapeutic effect through a decrease in catecholaminegic and serotoninergic turnover although new avenues have been opened by some recent reports indicating a facilitation of GABAergic and glycinergic transmission in CNS.

Animals↗
PubMed1989

Management of depression in the elderly.

Primary care physicians have a vital role to play in identifying depression in their elderly patients. Diagnosis may be difficult, because symptoms are atypical and frequently include psychomotor agitation, somatic symptoms, and complaints of memory loss. Patients with medical illnesses, such as cancer, postmyocardial infarction, stroke, Parkinson's disease, and early Alzheimer's disease are particularly vulnerable to depression. Drugs that may cause depressive symptoms are digitalis at toxic levels, beta-blockers, centrally acting antihypertensives, immunosuppressants, and nonsteroidal anti-inflammatory agents. Cyclic antidepressants are the drugs of first choice. Selection depends on the patient's physical health and current medications and the side effect profile of the drug. Side effects are more pronounced in old age because of drug accumulation owing to slowed clearance. Troublesome side effects are anticholinergic effects, orthostatic hypotension, sedation, cardiotoxicity, and weight gain. The most useful antidepressants for geriatric patients are the secondary amines, desipramine and nortriptyline. The second-generation drug trazodone has the advantage of causing the least anticholinergic effects, but it is very sedating. Before treatment, the patient should have an electrocardiogram, liver function tests, tonometry, sitting and standing blood pressures, evaluation of urinary symptoms for outflow obstruction, review of current medications, and estimation of suicide risk. Cyclic antidepressants are contraindicated during recovery from myocardial infarction, in heart disease when there is severe impairment of myocardial performance, in seizure disorders, and in the presence of glaucoma or a large prostate. Drug interactions that may cause trouble can occur with epinephrine, MAO inhibitors, thyroid hormone, cimetidine, and centrally acting antihypertensives. Dosage should start low, increasing usually by 25 mg every 4 to 5 days until a therapeutic level is reached. Failure of a noradrenergic antidepressant after 4 to 5 weeks can be followed by a trial of a serotonergic drug. Drug serum level monitoring is useful for imipramine, desipramine, and nortriptyline. Monoamine oxidase inhibitors are effective in many elderly patients who are resistant to TCAs. Sympathomimetic drugs must be avoided with MAOIs. Elderly patients are at high risk of toxicity and drug interactions with lithium. Electroconvulsive therapy is useful for patients who do not respond to drug treatment, but medical complications, particularly cardiovascular, often occur in patients 75 or older. Many patients relapse after ECT. Psychotherapy together with pharmacotherapy may be the optimal treatment for elderly depressives. Older patients are more likely to become chronically depressed than younger patients. The risk of suicide in depressed elderly males is high, particularly in those with psychosocial problems, and depression rises with age.

Aged↗
PubMed2006

[A case of tianeptine abuse].

Tianeptine is an antidepressant agent like the selective serotonin reuptake inhibitors (SSRIs). The anxiolytic efficacy of tianeptine is similar to that of tricyclic and tetracyclic antidepressants. Very few cases have been reported in connection with excessive consumption of tianeptine. Although it is not reconciled with results of many studies on excessive consumption of tianeptine, stimulant action has been specifically emphasized on some case reports of tianeptine abuse. These reports indicate that a tolerance is developed, there is a strong mode of feeling, and there are physical withdrawal symptoms if not taken again. Treatment with tianeptine can pose a risk for addicted patients in terms of high doses as well as tolerability. In this article, we report a 24-year-old patient who abused tianeptine for one year. The biological tolerance was excellent, and hepatic parameters were not affected. The patient experienced and seeks a psychostimulant effect. The patient had a previous history of addiction to cannabis, opiates and cocaine. We concluded that the effect of tianeptine and its addiction risk at the patient who had a history of addiction to multiple substances, and spontaneously increased dose of tianeptine during the last one year up to 3000 mg per day at present. In the literature, reports of addictions to antidepressants are scarce and most of them involve agents with amphetamine-like properties, including amineptine and tranylcypromine. Other reports involving other antidepressant agents, including amitriptyline, fluoxetine and tianeptine remain exceptional.

Adult↗
PubMed1984

Chronic and acute administration of typical and atypical antidepressants on activity of brain noradrenaline systems in the rat thiopentone anaesthesia model.

A behavioural model sensitive to manipulation of brain noradrenaline systems and with characteristics of beta-receptor mediation has been developed using the duration of thiopentone anaesthesia in the rat. Acute and chronic administration of various antidepressant agents was examined. In the acute phase, (30 min prior to thiopentone) the noradrenaline uptake-inhibiting tricyclic drugs and viloxazine increased anaesthesia duration in a dose-dependent fashion. The atypical antidepressants trazodone, iprindole, and mianserin did this only weakly, while the dopaminergic and serotonergic uptake-inhibiting antidepressants (respectively bupropion, nomifensine, and zimelidine, fluoxetine) markedly shortened anaesthesia duration. Chronic administration (for 15 days) prolonged anaesthesia duration measured 2 or 5 days after the last drug injection for all tricyclic agents, for the atypical antidepressants mianserin, iprindole, fluoxetine, and zimelidine, and for viloxazine.

Anesthesia↗
PubMed1996

The pharmacotherapy of panic disorder.

The biological model for panic disorder posits a specific, genetically inherent neurochemical dysfunction; pharmacological treatment attempts to reregulate the dysregulated physiological system, thereby achieving remission (or, ideally, recovery) or amelioration of the symptoms sufficient for nonpharmacological therapies to be viable. This article will review the evidence of the efficacy of single classes of pharmacological agents (antidepressants, including TCAs, MAOIs, and SSRIs; benzodiazepines; and other agents) and integrated treatments, involving coadministration of medications within or across classes or a combination of pharmacological and nonpharmacological therapies, such as cognitive-behavioral therapy. Research pertaining to the relative efficacy of administering combination treatments concurrently or sequentially is examined. Individualized treatment plans for patients maximize the benefits of integrated treatments.

Antidepressive Agents, Tricyclic↗