摘要:

There is considerable interest in the possible antidepressant properties of antiglucocorticoids. Studies of the hypothalamic-pituitary-adrenal (HPA) axis in depression. coupled with increasing recognition of the importance of glucocorticoids in brain function, strongly support such interest.Psychiatric symptomatology in Cushing's syndrome (a disorder involving hypersecretion of cortisol), the adverse cognitive effects of glucocorticoids, and the suppressive effects of conventional antidepressants on HPA function all suggest that HPA abnormalities could cause or contribute to depression. However. the psychiatric effects of glucocorticoids and glucocorticoid withdrawal suggest that HPA hyperactivity compensates for some other defect. While preliminary clinical studies suggest that both glucocorticoids and antiglucocorticoids may have efficacy in depression, the toxicity and loss of efficacy of available drugs during long term administration will probably necessitate the development of new agents to advance this field.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Experimental studies have indicated that the central histaminergic neuron system plays an important role in the inhibition of seizures through stimulation of histamine H1receptors, especially in the developmental period. This has therapeutic implications for currently available drugs that act at histamine receptors. H1receptor antagonists, including classical antihistamines and anti-allergy drugs, occasionally induce convulsions in healthy children and patients with epilepsy. In particular, promethazine, carbinoxamine, mepyramine (pyrilamine) and ketotifen should be used with caution in these patients. These drugs are widely used as components of over-the-counter medications. The use of thed-chlorphenamine (d-chlorpheniramine) activation study with EEG monitoring is useful for assessing the seizure susceptibility of patients who have had convulsions secondary to administration of H1receptor antagonists.H2receptor antagonists have also occasionally been reported to induce convulsions in critically ill and polymedicated patients, and patients with chronic renal or hepatic failure. However, experimental findings have not been consistent with these clinical reports, such that the role of these receptors and their ligands in inducing seizures cannot be confirmed.Recently, H3receptor antagonists, which enhance endogenous histamine release in the brain, have been demonstrated to have a potent anticonvulsant action. Therefore, these compounds may represent a new avenue for the development of antiepileptic drugs. Considering that H3receptor antagonists also induce arousal patterns on the EEG, it is possible that they will not be associated with the sedative effects of many conventional antiepileptic drugs.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Toxoplasmic encephalitis is a very common opportunistic infection in patients with AIDS (occurring in 5 to 15% of cases). It is the most frequent CNS manifestation in patients with previousToxoplasmainfection, as determined by the presence of specific antibodies.A diagnosis of toxoplasmic encephalitis should be suspected in patients who present with clinical symptoms such as fever, headaches or any neurological abnormalities associated with the presence of intracerebral abscess on computerised tomography scans and/or magnetic resonance imaging. Early diagnosis leading to early treatment is the best prognostic factor for this treatable, but severe, disease.The diagnosis is assessed by the response to therapy with a combination of pyrimethamine (50 mg/day) and sulfadiazine (4 g/day). which should lead to improvement within 5 to 10 days. The duration of acute therapy should be 3 to 6 weeks. A combination of pyrimethamine plus clindamycin is second-line therapy in patients who are intolerant of pyrimethamine and sulfadiazine (30 to 50% of cases). Maintenance therapy should be life-long to avoid relapses.The widespread use of primary prophylaxis with cotrimoxazole (trimethoprim-sulfamethoxazole) or a combination of dapsone plus pyrimethamine in patients who are positive for antitoxoplasmic antibodies and have a CD4+ lymphocyte count of less than 200 cells/μl (200 × 106cells/L) tends to decrease the incidence of toxoplasmic encephalitis. Physicians need to provide information to patients on the usefulness of primary prophylaxis to optimise compliance with treatments.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

In recent years, the frequency with which patients present with ‘double depression’, i.e. coexisting chronic depression (dysthymia)andacute major depression, has become increasingly evident. A growing research literature demonstrates that patients with double depression are at increased risk for poor outcome, including poor psychosocial functioning, high usage of medical services, high rates of suicide attempts, and increased recurrence of major depression. Furthermore, naturalistic studies have shown that when these patients are treated in the community, they often do not receive adequate antidepressant medication to treat their acute or chronic depressive disorders.In this article, we introduce a typology that is designed to assist clinicians in determining useful strategies in the short and long term treatment of double depression. This differentiates between those patients with double depression who present primarily with acute depression; those presenting primarily with chronic depression (where treatment can focus on the single, more severe disorder, and may be time-limited or episodic): and those presenting with severe acute depressionandsevere chronic depression, in whom lifelong medication is often required. Aggressive treatment is recommended for all patients with double depression, but refined treatment strategies based on depressive typology may help to increase compliance, consolidate therapeutic gains and forestall relapse.A growing psychopharmacology literature shows that several different classes of medication [tricyclic antidepressants, monamine oxidase inhibitors, selective serotonin (5-hydroxytryptamine: 5-HT) reuptake inhibitors and others] are effective in the treatment of double depression, although perhaps somewhat less effective than in the treatment of acute major depression.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Several early studies suggested that differences exist between antiepileptic drugs (AEDs) in terms of their propensity to cause adverse effects on cognitive functions, favouring carbamazepine over phenobarbital (phenobarbitone), phenytoin and valproic acid (sodium valproate). The combined results of recent studies in patients and healthy volunteers reveal that at therapeutic serum concentrations phenobarbital, phenytoin, carbamazepine, oxcarbazepine and valproic acid produce nearly comparable adverse effects on higher cognitive functions.The newer AEDs (with the exception of zonisamide and topiramate) appear to induced fewer cognitive adverse effects than the older agents. Furthermore, there is limited evidence that gabapentin, lamotrigine and vigabatrin may have beneficial effects on cognitive function. Some of the newer AEDs may also have neuroprotective effects that can prevent seizure-induced neuronal damage, and so reduce cognitive dysfunction. This is an important clinical consideration, as even modest differences between older and newer AEDs are relevant for patients.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Limitations of long term levodopa therapy for Parkinson's disease represent a major problem in the management of many patients. Dopamine receptor agonists provide antiparkinsonian effects and their use is most clearly defined in the context of complications from levodopa therapy. As such, dopamine receptor agonists are useful adjunctive agents to levodopa. Because typical adverse effects of dopamine receptor agonists may differ from those of levodopa, combination therapy is often effective and well tolerated.A variety of dopamine receptor agonists, both ergot and non-ergot derivatives, are useful in the treatment of Parkinson's disease. Five dopamine receptor agonists are currently available for use throughout much of the world, and many more are in developmental phases. Varying pharmacodynamic and pharmacokinetic profiles allow selection of appropriate dopamine receptor agonists for specific clinical scenarios. Recently reported comparative studies also suggest certain prescribing recommendations.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

SynopsisMirtazapine is a tetracyclic antidepressant with a novel mechanism of action; it increases noradrenergic and serotonergic neurotransmission via blockade of central &agr;2-adrenergic auto- and heteroreceptors. The increased release of serotonin (5-hydroxytryptamine; 5-HT) stimulates serotonin 5-HT1receptors because mirtazapine directly blocks 5-HT2and 5-HT3receptors. The enhancement of both noradrenergic- and 5-HT1receptor-mediated neurotransmission is thought to be responsible for the antidepressant activity of mirtazapine.In short term (5 to 6 weeks) clinical trials in patients with depression. mirtazapine produces clinical improvements significantly superior to those of placebo, similar to those of tricyclic antidepressants (TCAs) [amitriptyline, clomipramine and doxepin] and possibly superior to those of trazodone.Short term clinical tolerability data suggest that mirtazapine produces fewer anticholinergic-, adrenergic- and serotonergic-related adverse events than TCAs. In rare cases, mirtazapine, in common with many antidepressants, was associated with potentially serious changes in haematological parameters (e.g. agranulocytosis and neutropenia). The drug appears to be safe in overdose and possesses a very low propensity for inducing seizures.Comparisons with other classes of antidepressants are needed to determine the relative position of mirtazapine in clinical practice. However, preliminary data indicate that mirtazapine, with its novel mechanism of action, is a promising addition to currently available options for the treatment of depression.Pharmacodynamic PropertiesIn vitroneurochemical studies have demonstrated that mirtazapine blocks central &agr;2-adrenergic auto- and heteroreceptors, but has no effect on noradrenaline (norepinephrine) reuptake. The affinity of the drug was 10-fold higher for central presynaptic &agr;2-adrenoceptors than for central postsynaptic and peripheral &agr;2-adrenoceptors, and 30-fold higher for &agr;2-adrenoceptors than for &agr;1-adrenoceptors. Microdialysis and neurophysiological experiments as well as behavioural studies performed in rats support the &agr;2-adrenoceptor antagonist properties of mirtazapine.Receptor binding studies have shown that mirtazapine has a high affinity for serotonin 5-HT2and 5-HT3receptors, central and peripheral histamine H1receptors and a low affinity for 5-HT1, dopaminergic and muscarinic cholinergic receptors. Its activity at serotonin receptor subtypes has been confirmed in animal behaviour models.Mirtazapine activates 5-HT1receptor-mediated serotonergic neurotransmission by enhancing the stimulatory effect of the noradrenergic system on serotonergic cell firing (an &agr;1-adrenoceptor-mediated effect) as well as antagonising the inhibitory effect of the noradrenergic system on serotonin release (an &agr;2-adrenoceptor-mediated effect). Electrophysiological experiments have demonstrated that mirtazapine enhances serotonergic transmission through blockade of presynaptic &agr;2-adrenoceptors. The drug does not inhibit serotonin reuptake.Pharmacokinetic PropertiesThe bioavailability of mirtazapine is approximately 50%. Peak plasma concentrations are reached within 2.2 to 3.1 hours after single oral doses of 15 to 75mg and are dose-dependent. Mirtazapine is extensively metabolised in the liver; up to 85% of the drug is eliminated in the urine (up to 4% as unchanged drug) and the remaining 15% is eliminated in the faeces. The mean elimination half-life of mirtazapine is approximately 22 hours, making it suitable for once-daily administration.Therapeutic PotentialIn randomised double-blind comparative trials including patients with major depression, short term (5 to 6 weeks) therapy with mirtazapine was significantly more effective than placebo, as effective as amitriptyline, clomipramine and doxepin, and at least as effective as trazodone.Results from a meta-analysis of 5 comparative trials in which 60% of patients were hospitalised with severe depression [mean baseline 17-item Hamilton Depression Rating Scale (HAMD) score ≥25] revealed no significant differences between mirtazapine and amitriptyline. The responder rates (≥50% decrease in HAMD score from baseline) at 6 weeks and study end-point were 70 and 61%, respectively, for mirtazapine and 73 and 64%, respectively, for amitriptyline.In a comparative trial in older outpatients (mean age 61 to 63 years), reductions in rating scale scores of depression and the percentage of responders tended to be higher in mirtazapine than in trazodone recipients.TolerabilityThe tolerability profile of mirtazapine is based on results from short term (5 to 6 weeks) comparisons with placebo and other antidepressants; no longer term data are available.Drowsiness (23vs14%). excessive sedation (19vs5%), dry mouth (25vs16%), increased appetite (11vs2%) and bodyweight gain (10vs1%) occurred significantly more frequently with mirtazapine in placebo-controlled trials. Analysis of blood pressure, heart rate and symptoms of sexual dysfunction indicated no significant differences between mirtazapine and placebo recipients.In a meta-analysis, mirtazapine appeared to be better tolerated than amitriptyline, with significantly fewer patients experiencing anticholinergic (dry mouth, constipation, and abnormal accommodation and vision), cardiac (palpitations and tachycardia) and neurological (tremor and vertigo) adverse events. Mirtazapine was at least as well tolerated as clomipramine, doxepin and trazodone in comparative trials and appeared to be associated with slightly lower incidences of anticholinergic and neurological adverse events than these drugs.Clinical trial and postmarketing surveillance data suggest that mirtazapine has a very low potential for inducing seizures. Excessive but transient somnolence was the only symptom noted in 10 patients taking an overdose (up to 315mg) of mirtazapine.Mirtazapine is infrequently associated with clinically relevant changes in laboratory parameters. Granulocytopenia and elevated alanine aminotransferase levels have been reported; most were mild in severity and returned to normal values with continued administration of mirtazapine. Elevated cholesterol levels (mean 3 to 4%) have also been reported.Dosage and AdministrationThe recommended starting dosage of mirtazapine is 15 mg/day for 4 days, then 30 mg/day for 10 days. If effective, the drug should be continued unchanged at this dosage or, in patients assessed as insufficiently improved, the daily dosage may be further increased to 45 mg/day. In patients with hepatic or renal insufficiency, careful dosage titration as well as regular and close monitoring for adverse events is recommended. Concomitant use of mirtazapine and diazepam or alcohol (ethanol) may also impair cognitive and/or motor performance.

ISSN:1172-7047    

出版商:ADIS    

年代:1996

数据来源: ADIS