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Seven of the newest antidepressants are the serotonin-selective reuptake inhibitors (fluoxetine, sertraline, paroxetine, and fluvoxamine [currently approved in the United States only for obsessive-compulsive disorder]), a serotonin-norepinephrine reuptake inhibitor (venlafaxine), a postsynaptic serotonin antagonist-presynaptic serotonin reuptake inhibitor (nefazodone), and a presynaptic-postsynaptic noradrenergic-serotonergic receptor antagonist (mirtazapine). Many of these drugs are potent inhibitors of the cytochrome P-450 enzymes (CYPs) of the liver. The isoforms of the CYPs most relevant to the use of antidepressants are CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP inhibition may affect the metabolism of numerous drugs in several classes that are substrates for these isoenzymes, with potentially serious consequences. To minimize the potential for an adverse event, the practitioner must remember the drug-drug interactions, and possible consequences when one of these antidepressants is being prescribed. A \"primer\" on drug metabolism is included herein, which serves as a basis for understanding these interactions., Each of the isoenzymes of the CYPs is discussed in relationship to the drugs they metabolize, and appropriate cautions are recommended for concurrent administration of these new antidepressants and other drugs most frequently prescribed to elderly patients.

BACKGROUND: The discontinuation of many pharmacologic agents is associated with characteristic withdrawal symptoms. Antidepressants, particularly the tricyclic antidepressants (TCAs), are known to be associated with a group of common symptoms upon discontinuation. Serotonin reuptake inhibitors (SRIs) are also taking their respective place in the literature with reports of discontinuation symptoms. This review summarizes case reports and reports that allow systematic assessment of discontinuation symptoms following SRI discontinuation.
METHODS: A computerized literature search was conducted using a MEDLINE search to identify reports of withdrawal effects following discontinuation of SRIs. Additional reports were found in the bibliographies of various published reports.
RESULTS: SRI discontinuation symptoms in adults are summarized in 24 case reports and 9 reports from controlled clinical trials. Additionally, 3 case reports addressing SRI discontinuation in the neonate are described. The reports describe clusters of symptoms commonly associated with the discontinuation of an SRI.
CONCLUSIONS: We propose to define an antidepressant discontinuation syndrome as the onset of a cluster of somatic and psychic symptoms following the discontinuation of an SRI and not attributable to other causes (e.g., concomitant medication, illness). These symptoms include dizziness, light-headedness, insomnia, fatigue, anxiety/agitation, nausea, headache, and sensory disturbance. The syndrome may last up to 3 weeks and may be improved by restarting the antidepressant or starting an antidepressant with a similar pharmacologic profile.

Selective serotonin reuptake inhibitors have gained widespread use in the treatment of depression. A 78-year-old woman became hyponatremic 3 days after being treated with sertraline and was subsequently diagnosed with the syndrome of inappropriate antidiuretic hormone (SIADH). She became symptomatic, but experienced rapid resolution of the laboratory and clinical abnormalities associated with SIADH on discontinuing sertraline and receiving fluid restriction, hypertonic saline, and demeclocycline. Several mechanisms may relate SIADH and vasopressin release to serotonin.

OBJECTIVE: To review reported cases of hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with the use of selective serotonin reuptake inhibitors (SSRIs).
METHODS: A search of MEDLINE for reports of hyponatremia and SIADH associated with the use of fluoxetine, fluvoxamine, paroxetine or sertraline published between January 1980 and May 1995. Unpublished reports of cases were requested from the pharmaceutical industry, the Ontario Medical Association, the Health Protection Branch of Health Canada, the US Food and Drug Administration and the World Health Organization.
METHODS: Spontaneous reports from postmarketing surveillance.
RESULTS: A total of 736 cases of hyponatremia [corrected] and SIADH associated with SSRI use were reported. Fluoxetine was involved in 554 (75.3%) of the cases, paroxetine in 91 (12.4%), sertraline in 86 (11.7%) and fluvoxamine in 11 (1.5%). Reports of 30 cases were published. The remaining 706 cases were reported to monitoring bodies and the pharmaceutical industry. According to information in the published reports, the median time to onset of hyponatremia was 13 days (range 3 to 120 days). Most (83%) of the published cases involved patients 65 years of age or more, as compared with 74% of the unpublished cases.
CONCLUSIONS: Elderly people may be at increased risk for hyponatremia associated with SSRI use. Physicians caring for elderly patients should be aware of this potentially serious but reversible adverse effect. Further research is required to determine the incidence of this adverse effect, the relative risk of hyponatremia and SIADH in different age groups and the risk associated with different SSRI drugs.

The clinical use of sertraline for 1 year in a family practice clinic in a small Air Force hospital was reviewed. Retrospective chart review showed that 85% of patients receiving five or more prescriptions for sertraline had a diagnosis of depression; the remainder were treated for chronic pain or dysthymia. The patients in the review needed dose increases (above the recommended starting dose of 50 mg qd) in nearly 50% of the cases. Clinicians using sertraline for the treatment of affective illness in the primary care setting should be aware of the likelihood for dose increases to achieve maximal clinical benefit.

Obsessive compulsive disorder (OCD) is a prevalent form of psychopathology in the elderly, yet limited evaluation of the disorder in this age group has occurred. We review the literature and describe a case of OCD effectively treated in an 80-year-old man. Case study reports suggest that elderly persons are responsive to selective serotonin uptake inhibitors, although medication selection and dosage may need to be adjusted as a result of the medical conditions sometimes present in the elderly. Elderly persons appear able to benefit from exposure and response prevention, although behavioral intervention has not been frequently used. We describe here the first case report where exposure and response prevention procedures were successfully used and this intervention was not confounded with psychopharmacologic treatment.

BACKGROUND: A review of the efficacy of antidepressant drug treatment in patients with obsessive-compulsive disorder (OCD), using a meta-analytic approach.
METHODS: Randomised double-blind clinical trials of antidepressant drugs, carried out among patients with OCD and published in peer-reviewed journals between 1975 and May 1994, were selected together with three studies currently in press. Forty-seven trials were located by searching the Medline and Excerpta Medica-Psychiatry data bases, scanning psychiatric and psychopharmacological journals, consulting recent published reviews and bibliographies, contacting pharmaceutical companies and through cross-references. Hedges\' g was computed in pooled data at the conclusion of treatment under double-blind conditions or at the latest reported point of time during this treatment period. For each trial, effect sizes were computed for all available outcome measures of the following dependent variables: obsessive-compulsive symptoms considered together; obsessions; compulsions; depression; anxiety; global clinical improvement; psychosocial adjustment; and physical symptoms.
RESULTS: Clomipramine was superior to placebo in reducing both obsessive-compulsive symptoms considered together (g = 1.31; 95% CI = 1.15 to 1.47) as well as obsessions (g = 0.89, 95% CI = 0.36 to 1.42) and compulsions (g = 0.79; 95% CI = 0.34 to 1.24) taken separately. Also, selective serotonin re-uptake inhibitors (SSRIs) as a class were superior to placebo, weighted mean g being respectively 0.47 (95% CI = 0.33 to 0.61), 0.54 (95% CI = 0.34 to 0.74) and 0.52 (95% CI = 0.34 to 0.70) for obsessive-compulsive symptoms considered together, and obsessions and compulsions taken separately. Although on Y-BOCS the increase in improvement rate over placebo was 61.3%, 28.5%, 28.2% and 21.6% for clomipramine, fluoxetine, fluvoxamine, and sertraline respectively, the trials testing clomipramine against fluoxetine and fluvoxamine showed similar therapeutic efficacy between these drugs. Finally, both clomipramine and fluvoxamine proved superior to antidepressant drugs with no selective serotonergic properties.
CONCLUSIONS: Antidepressant drugs are effective in the short-term treatment of patients suffering from OCD; although the increase in improvement rate over placebo was greater for clomipramine than for SSRIs, direct comparison between these drugs showed that they had similar therapeutic efficacy on obsessive-compulsive symptoms; clomipramine and fluvoxamine had greater therapeutic efficacy than antidepressant drugs with no selective serotonergic properties; concomitant high levels of depression at the outset did not seem necessary for clomipramine and for SSRIs to improve obsessive-compulsive symptoms.

Sertraline is a member of a new class of psychotherapeutic agents that selectively inhibit serotonin reuptake in the brain. Animal studies have demonstrated that inhibition of serotonin reuptake leads to enhanced serotonergic neurotransmission and indirectly results in a down-regulation of beta-adrenoceptors. The preclinical pharmacology of sertraline predicts antidepressant activity without accompanying anticholinergic, cardiotonic, or sedative side effects. Recent laboratory and clinical observations pertaining to body weight and obsessive compulsive disorder suggest the possibility of broader clinical indications for selective serotonin reuptake blockers such as sertraline.

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