Drugs online research references
J Affect Disord. 1998 May;49(2):141-4.
The SSRI antidepressants: exploring their "other" possible properties.
Andrews W, Parker G, Barrett E.
Psychiatry Unit, Prince of Wales Hospital, Sydney, Australia.
BACKGROUND: Anecdotal reports suggest that the SSRIs may have important properties in addition to their antidepressant effects, possibly modifying mediating variables that dispose to and maintain depression. This preliminary study seeks to identify any such potential variables. METHODS: Fifty three subjects who had reported substantial general benefit to their clinician after treatment with an SSRI were requested to retrospectively rate change across a range of constructs assessed by questionnaire. RESULTS: Differential effects were identified. Irritability, trait depression, worry and neuroticism scores showed the most marked improvement, with cognitive style components also showing significant positive change. Equally importantly, there was no evidence of a positive response bias across all constructs. CONCLUSION: We suggest that the SSRIs may act as "antiworry" agents and reduce irritability, neuroticism and dysfunctional attributions. LIMITATIONS: Our study was retrospective and relied on self-report by volunteer patients who had been previously depressed. The study design cannot exclude the possibility that improvement reported on a number of measures may have been due to the amelioration of residual depression. CLINICAL RELEVANCE: The SSRIs, recognised as having antidepressant and anti-obsessional properties, may also have the capacity to lower irritability, worrying and neuroticism. This capacity could be useful per se but may, in addition, reduce the occurrence and duration of depressive episodes, particularly by reducing "anxious worrying".
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9609678&dopt=Abstract
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J Clin Psychopharmacol. 1998 Jun;18(3):198-207.
Determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition by paroxetine and fluvoxamine in vivo.
Ozdemir V, Naranjo CA, Shulman RW, Herrmann N, Sellers EM, Reed K, Kalow W.
Sunnybrook Health Science Centre, Department of Pharmacology, University of Toronto, Ontario, Canada.
Major depression may require antidepressant treatment for several years. This necessitates consideration of the long-term effects of antidepressants on multiple clinical endpoints. The antidepressants paroxetine and fluvoxamine are potent in vitro inhibitors of CYP2D6 and CYP1A2 isozymes, respectively. CYP2D6 and CYP1A2 are important for the clearance of 30 or more frequently used medications. Moreover, CYP1A2 also contributes to metabolism of 17beta-estradiol and metabolic activation of environmental procarcinogens (e.g., arylamines in cigarette smoke). The aim of this study was to assess the determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition during paroxetine and fluvoxamine treatment. Healthy volunteers and patients received caffeine (100 mg) and dextromethorphan (30 mg) at baseline and at steady state of paroxetine (10-20 mg/day, 5-74 days, N = 13) or fluvoxamine (50-100 mg/day, 5-43 days, N = 8). The caffeine metabolic ratio (CMR) and the log O-demethylation ratio (ODMR) of dextromethorphan in overnight urine were used as in vivo indices of the CYP1A2 and CYP2D6 isozyme activities, respectively. All subjects had an extensive metabolizer phenotype for CYP2D6. After fluvoxamine treatment, baseline CMR 5.1 +/- 1.4 (mean +/- SD) decreased to 2.7 +/- 1.1 (p < 0.01). Paroxetine did not have a significant effect on CMR (p > 0.05). In seven of eight subjects in the fluvoxamine group, posttreatment CMR was comparable with the minimum CMR value (2.0) attainable in nonsmoking healthy volunteers. After paroxetine treatment, log ODMR changed from a baseline value of -2.28 +/- 0.37 to -1.13 +/- 0.44, indicating significant inhibition of CYP2D6 (p < 0.001). Subjects' CYP2D6 phenotype did not change after paroxetine treatment. Fluvoxamine had no significant effect on log ODMR (p > 0.05). The extent of inhibition of CYP2D6 and CYP1A2 by paroxetine and fluvoxamine, respectively, displayed a positive correlation with baseline enzyme activity (p < 0.05). In addition, a negative association was found between the plasma paroxetine concentration and the CYP2D6 activity after paroxetine treatment (r = -0.47, p < 0.05). These data indicate that paroxetine and fluvoxamine treatment with minimum clinically effective doses significantly inhibit CYP2D6 and CYP1A2, respectively. The extent of inhibition of CYP2D6 by paroxetine and of CYP1A2 by fluvoxamine is dependent in part on the baseline enzyme activity. The interindividual variability in CYP2D6 inhibition by paroxetine can also be explained by variability in plasma paroxetine concentration. Most patients treated with fluvoxamine (50-100 mg/day) will reach population minimums for CYP1A2 activity. These results have potential implications for interindividual variability in the risk for drug-drug interactions mediated by CYP2D6 and CYP1A2 as well as for the disposition of 17beta-estradiol and environmental procarcinogens.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9617978&dopt=Abstract
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Neurochem Int. 2000 Feb;36(2):91-6.
Effect of chronic paroxetine treatment on 5-HT1B and 5-HT1D autoreceptors in rat dorsal raphe nucleus.
Davidson C, Stamford JA.
Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, Whitechapel, London, UK.
This study reports the effect of chronic paroxetine (10 mg/kg p.o., 21 days) on 5-HT1B and 5-HT1D autoreceptors controlling stimulated 5-HT efflux in slices of rat dorsal raphe nucleus. Electrically evoked 5-HT (10 pulses, 200 Hz, 0.1 ms, 10 mA) was measured using fast cyclic voltammetry. 5-HT efflux was inhibited by CP 93129 (10 nM-10 microM) and by sumatriptan (1 nM-1 microM) agonists at 5-HT1B and 5-HT1D receptors, respectively. Chronic paroxetine did not, initially, appear to alter the sensitivity of the 5-HT1B autoreceptors to CP 93129. However, when constructed in the presence of WAY 100635 (10 nM) the selective and silent 5-HT1A antagonist, there was a significant (P < 0.001) rightward shift of the CP 93129 concentration-response curve in the paroxetine-treated rats but not in the controls, implying a desensitisation of the 5-HT1B autoreceptor by paroxetine. Chronic paroxetine did not affect the sumatriptan concentration-response curve, even with WAY 100635 present, implying that there was no (de)sensitisation of the 5-HT1D autoreceptor. These data suggest that chronic paroxetine treatment may desensitise 5-HT1B autoreceptors in the dorsal raphe nucleus but that this effect is unmasked only when the dominant 5-HT1A autoreceptor control is antagonised.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10676872&dopt=Abstract
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