Re: The use of selective serotonin reuptake inhibitors in the elderly

A case of small cell carcinoma of the prostate without a primary lesion in the lung was reported. The cancer was diagnosed after the patient complained of lumbago caused by bone metastasis. The tumor was 5.9 x 5.0 x 4.6 cm. The patient was treated with 4 courses of chemotherapy using cisplatin and etoposide. The tumor diminished to 4.0 x 4.0 x 3.5 cm after completion of the 4 courses of treatment. Prostatic antigen levels were less than 1.0 ng/mL during the therapy. Neuron-specific enolase levels were 35.9 ng/mL at the beginning of therapy, and decreased to 7.4 ng/mL after completion of 4 courses of treatment. The patient died 3 months after the completion of treatment. This regimen had some value for inhibiting the growth of small cell carcinoma.     

Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors

The recently introduced antidepressants, the selective serotonin reuptake inhibitors (SSRIs) [citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline], are known for their clinical efficacy, good tolerability and relative safety. They differ from each other in chemical structure, metabolism and pharmacokinetic properties. Therapeutic drug monitoring of these compounds is not widely used, as the plasma concentration ranges within which clinical response with minimal adverse effects appears to be optimal are not clearly defined. Almost all recent assays developed for the quantitative determination of SSRIs and their metabolites in blood are based either on the separation of SSRIs by high performance liquid chromatography (HPLC) or gas chromatography (GC). Citalopram and fluoxetine have been introduced as racemic compounds. There are some differences in the pharmacological profile, metabolism and pharmacokinetics between the enantiomers of the parent compounds and their demethylated metabolites. Stereoselective chromatographic methods for their analysis in blood are now available. With regard to the SSRIs presently available, no clearcut plasma concentration-clinical effectiveness relationship in patients with depression has been shown, nor any threshold which defines toxic concentrations. This may be explained by their low toxicity and use at dosages where serious adverse effects do not appear. SSRIs vary widely in their qualitative and quantitative interaction with cytochrome P450 (CYP) isozymes in the liver. CYP2D6 is inhibited by SSRIs, in order of decreasing potency paroxetine, norfluoxetine, fluoxetine, sertraline, citalopram and fluvoxamine. This may have clinical consequences with some but not all SSRIs, when they are taken with tricyclic antidepressants. Except for citalopram and paroxetine, little is known about the enzymes which control the biotransformation of the SSRIs. There have been many reports on marked pharmacokinetic interactions between fluoxetine and tricyclic antidepressants. Fluoxetine has a stronger effect on their hydroxylation than on their demethylation. Interactions observed between fluoxetine and alprazolam, midazolam and carbamazepine seem to occur on the level of CYP3A. Fluvoxamine strongly inhibits the N-demethylation of some tricyclic antidepressants of the tertiary amine type and of clozapine. This may lead to adverse effects but augmentation with fluvoxamine can also improve response in very rapid metabolisers, as it increases the bioavailability of the comedication. Fluvoxamine inhibits with decreasing potency, CYP1A2, CYP2C19, CYP2D6 and CYP1A1, but it is also an inhibitor of CYP3A. Fluoxetine and fluvoxamine have shown to increase methadone plasma concentrations in dependent patients. Some authors warn about a combination of monoamine oxidase (MAO) inhibitors with SSRIs, as this could lead to a serotonergic syndrome. Studies with healthy volunteers suggest, however, that a combination of moclobemide and SSRIs, such as fluvoxamine, should not present serious risks in promoting a serotonin syndrome. A combination of moclobemide and fluvoxamine has successfully been used in refractory depression, but more studies are needed, including plasma-concentration monitoring, before this combined treatment can be recommended. Paroxetine is a substrate of CYP2D6, but other enzyme(s) could also be involved. Its pharmacokinetics are linear in poor metabolisers of sparteine, and non-linear in extensive metabolisers. Due to its potent CYP2D6 inhibiting properties, comedication with this SSRI can lead to an increase of tricyclic antidepressants in plasma, as shown with amitriptyline and trimipramine. CYP3A has been claimed to be involved in the biotransformation of sertraline to norsertraline. Clinical investigations (with desipramine) confirmed in vitro findings that CYP2D6 inhibition by sertraline is only moderate. (ABSTRACT TRUNCATED)     

Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis

BACKGROUND: The use of antidepressant medications and the resulting costs have increased dramatically in recent years, partly because of the introduction of selective serotonin reuptake inhibitors (SSRIs). An assessment of the clinical and economic aspects of SSRIs compared with the older tricyclic antidepressants (TCAs) was initiated to generate information for purchasers of these drugs as well as clinicians. One component of this study was an examination of the adverse effects associated with the use of these drugs. METHODS: Searches of bibliographic databases (for January 1980 through May 1996) and manual scanning of both peer-reviewed publications and other documents were used to identify double-blind, randomized controlled trials involving at least one SSRI and one TCA. For the study of adverse effects, only trials that had at least 20 patients in each trial arm and that reported rates of adverse effects in both arms were retained. In total 84 trials reporting on 18 adverse effects were available. Meta-analyses were undertaken to calculate pooled differences in rates of adverse effects. The question of whether the method of eliciting information from patients about adverse effects made a difference in the findings was also examined. Finally, differences in drop-out rates due to adverse effects were calculated. RESULTS: The crude rates of occurrence of adverse effects ranged from 4% (palpitations) to 26% (nausea) for SSRIs and from 4% (diarrhea) to 27% (dry mouth) for TCAs. The differences in the rates of adverse effects between the 2 types of drugs ranged from 14% more with SSRIs (for nausea) to 11% more with TCAs (for constipation). The results did not depend on the method of eliciting information from patients. There were no statistically significant differences between drug classes in terms of drop-outs due to adverse effects. INTERPRETATION: SSRIs and TCAs are both associated with adverse effects, although the key effects differ between the drug classes. Further explanation of the adverse effects and their relation to discontinuation of medication will require better studies involving prospective collection of quality-of-life data.     

Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety

The selective serotonin reuptake inhibitors (SSRIs) are now being employed in the treatment of the full spectrum of anxiety disorders. In comparative trials, the SSRIs are proving to be equal or superior in efficacy to traditional antianxiety medications. Due to their favorable side effect profile, safety, and tolerability, they are rapidly replacing older agents in the treatment of anxiety. Neuroanatomical pathways that may be important in the antianxiety effect of the SSRIs are outline and discussed, followed by a review of the clinical evidence supporting the efficacy of this class of medications in the treatment of anxiety disorders.     

The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain

Using a tensiometer in accordance with the drop volume principle, the surface tension decrease with time was determined for whole and for 2%, 10%, and 50% aqueous solutions of saliva from one healthy donor. The reduction of surface tension with time was also measured for 10% and 20% saliva solutions with added samples of Streptococcus salivarius KRF2, S. sanguis KRF3, and Actinomyces naeslundii 2t-55. The results show that 1) there is a time dependence of the surface tension reduction of both whole saliva and diluted saliva, 2) an increase of the concentration of whole saliva in salivary solutions gives rise to larger and more rapid surface tension reduction, 3) the proteinaceous components of saliva appear to have a dominant contribution on surface tension in whole saliva and diluted saliva, and 4) the surface-active proteinaceous components in saliva have the ability to dominate the air-saliva interface also in the presence of high concentrations of salivary bacteria.     

Hyponatraemia associated with the use of selective serotonin re-uptake inhibitors

A man with a 15-year history of non-Hodgkin's lymphoma presented with disseminated herpes zoster which initially responded to aciclovir. This was shortly followed by an acute exacerbation in the sites previously affected which was apparently resistant to antiviral therapy. Biopsy revealed a dense monomorphic lymphocytic infiltrate below active herpes zoster which had the same morphology and immunoreactivity as the underlying lymphoma. His clinical condition resolved with further chemotherapy for his lymphoma and continued treatment with aciclovir.     

Cost-benefit & cost-effectiveness analysis of the rapid onset of selective serotonin reuptake inhibitors by augmentation

The cytoskeleton of the parabasalid protozoan Holomastigotoides was investigated by epifluorescence, scanning confocal, and transmission electron microscopy using antibodies to centrin, tubulin, and MPM-2 epitopes. Previous microscopic analysis of Holomastigotoides spp. has shown that up to 10,000 flagella are arranged in 2-8 spiral bands encircling the cell. Spindle poles are associated with two flagellar bands. Sheets of cytoplasmic microtubules (MTs) called axostyles originate in the cell apex and extend to the cell base. Antibodies to centrin, a member of the EF-hand family of calcium-binding proteins, labeled a number of structures in Holomastigotoides, namely axostyles, the mitotic spindle, and portions of flagellar bands. The identity of these structures was confirmed by transmission electron microscopy and by immunofluorescence microscopy using antibodies to tubulin and MPM-2 epitopes. Antibodies to tubulin labeled MTs in basal bodies, flagella, axostyles, and the mitotic spindle. MPM-2 antibodies labeled spindle poles and short segments of flagellar bands to which the spindle poles are attached. Centrin is known to show calcium-sensitive contractile behavior. The pattern of flagellar band staining by antibodies to centrin was affected by [Ca2+]. In detergent-extracted cell fragments, the centrin staining pattern could be changed by changing [Ca2+]. This Ca2+ effect was modulated by a monoclonal antibody to centrin (20H5), indicating that centrin plays a role in altering flagellar band structure. These results show that centrin is located in key positions for maintaining cell polarity and directing cell movement through interactions with other cytoskeletal elements. Calcium may regulate the morphology of centrin-containing structures.     

General practitioners' perceptions of the tolerability of antidepressant drugs: a comparison of selective serotonin reuptake inhibitors and tricyclic antidepressants

OBJECTIVE: To examine inceptions and discontinuations of antidepressants in general practice. DESIGN: An observational study analysing data from an ongoing cross sectional postal survey. Every three months a representative sample of 250 doctors recorded prescribing activity for four weeks. This provided 4000 general practitioner weeks of recording per year. SETTING: A representative panel of general practitioners in England, Wales, and Scotland. SUBJECTS: Patients who began a new course of an antidepressant or had their treatment stopped or changed by the general practitioner between 1 July 1990 and 30 June 1995. MAIN OUTCOME MEASURES: Numbers of patients prescribed a new course of antidepressant; numbers discontinuing treatment; the ratio of antidepressant discontinuations to antidepressant inceptions; reasons for discontinuation; proportion of switches to another antidepressant. RESULTS: There were 13,619 inceptions and 3934 discontinuations of selective serotonin reuptake inhibitors and tricyclic antidepressants during the study. The number of newly prescribed courses of antidepressants increased by 116%, mostly due to an increase in prescribing of serotonin reuptake inhibitors. The ratio of total discontinuations to inceptions was significantly lower for serotonin reuptake inhibitors (22%) than for tricyclic antidepressants (33%). Differences persisted when controlled for age and sex of patients and severity of depression. However, there was more switching away from selective serotonin reuptake inhibitors when they failed (72%) than from tricyclic antidepressants (58%). CONCLUSIONS: Selective serotonin reuptake inhibitors are less likely than tricyclic antidepressants to be discontinued. A prospective study is needed in general practice to assess the implications of differences in discontinuation rates and switches on clinical and economic outcomes.     

Cardiac side-effects of two selective serotonin reuptake inhibitors in middle-aged and elderly depressed patients

Selective serotonin reuptake inhibitors (SSRIs) are the 'new' drugs of first choice for the treatment of depression in the older patient. Systematic studies on the effects of SSRIs on cardiac function are scarce, despite the high prevalence of cardiac disorders in the older depressed patient. This is a study which systematically assessed cardiac function by echocardiography in middle-aged and elderly depressed patients treated with SSRI. In a double-blind randomized trial, 20 patients were assigned to receive fluvoxamine 100 mg/day [DOSAGE ERROR CORRECTED] or fluoxetine 20 mg/day [DOSAGE ERROR CORRECTED] for 6 weeks. Cardiac function was assessed by left ventricle ejection fraction, aortic flow integral and early or passive/late or active mitral inflow, and electrocardiography. Neither SSRI significantly affected cardiac function. Compared with patients without a history of myocardial infarction and/or hypertension, patients with such a history showed a significant improvement in left ventricular ejection fraction. Despite our small study sample, these data indicate that both fluoxetine and fluvoxamine do not affect cardiac function adversely.     

Nutritional implications of xerostomia and rampant caries caused by serotonin reuptake inhibitors: a case study

Serotonin reuptake inhibitors, such as fluoxetine, fenfluramine, and dexfenfluramine, are frequently used to treat obesity, depression, and bulimia. A common side effect of these medications is xerostomia, or dry mouth. A case study demonstrating the impact of drug-induced xerostomia on oral health and subsequent nutrition implications is presented. Rampant caries can result from a combination of xerostomia and inappropriate dietary and oral hygiene habits. Preventive dietary and dental guidelines are presented to assist nutrition and dental professionals in treating and counseling patients with xerostomia.     

Successful outcome in a patient with chemical sensitivity. Treatment with psychological desensitization and selective serotonin reuptake inhibitor

A 49-year-old male was diagnosed as having primary aldosteronism at age 39, and he was treated with antihypertensive drugs. In 1995, a computed tomogram revealed a mass in the right adrenal gland. Radiological examinations and endocrinological data revealed the presence of a pheochromocytoma in the right and an adrenocortical tumor in the left adrenal gland. Right adrenalectomy and left partial adrenalectomy were performed. Histologically, the right adrenal mass was compatible with pheochromocytoma, and the left adrenal mass was an adrenocortical adenoma. Endocrinological data as well as blood pressure returned to normal after operation.     

Hypertensive disorders of pregnancy and maternal and foetal outcome: a case controlled study

A case controlled prospective study of 250 cases of hypertension complicating pregnancy (study group) and 400 normal pregnant women (control group) was carried out to determine the effect of hypertension on maternal and foetal outcome. Pregnancy induced hypertension was present in 96% cases and chronic hypertension in 4% cases. Preterm delivery (28.8% versus 3%), labour induction rate (52.8% versus 3.25%), caesarean section rate (14.8% versus 3.5%), stillbirth rate (4.8% versus 0.25%) and overall perinatal mortality rate (14.8% versus 1%) were higher in study group compared to controls. In study group (40%) babies required special nursery care compared to controls (6.75%). From these results it can be concluded that maternal hypertension is associated with adverse pregnancy outcome.     

Octreotide in the prevention of hyperamylasemia following ERCP (a controlled multicenter study)

The aim of the multicentric trial was to study the effect of octreotide (Sandostatin) on the rise of pancreatic amylase in the serum after ERCP based on a large number of patients. The study was carried out in a prospective random manner in 2102 patients in 11 endoscopic centers. Patients in the treated group received 0.1 mg octreotide acetate, and those of the nontreated (control) group received isotonic sodium-chloride subcutaneously before the ERCP and 45 minutes after. Serum amylase and blood sugar were checked before the endoscopic procedure, 6 and 24 hours later. Out of the total number of patients involved, data of 1199 patients (599 in the treated group, and 600 in the control group) were evaluated. Octreotide diminished the percentual increase of serum amylase levels following ERCP. However, the frequency of hyperamylasaemia was decreased only after in patients with chronic obstructive pancreatitis or in such patients after endoscopic sphincterotomy. The peak serum level of blood sugar was higher in the treated group compared to the controls. There was no difference in the clinical symptoms following ERCP between the two groups. Conclusion: the prophylactic use of long-acting somatostatin may diminish the frequency of hyperamylasemia after ERCP in patients with chronic obstructive pancreatitis or in those patients who subsequently underwent EST.     

Design and synthesis of new potent, silent 5-HT1A antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors

Hybrid molecules built up by covalent coupling of aminopropanol derivatives (especially pindolol) with antidepressant drugs like fluoxetine, paroxetine or milnacipran were found to be potent and silent 5-HT1A antagonists (KB < 1 nM for 7c and 9a).     

The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes

The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 microM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.     

Fish on prozac: Effect of serotonin reuptake inhibitors on cognition in goldfish.

[Correction Notice: An erratum for this article was reported in Vol 122(4) of Behavioral Neuroscience (see record 2008-09788-005). In the aforementioned article, Figures 2, 3, and 4 are incorrect. The correct figures are printed in the erratum.] The authors studied the effect of fluoxetine (a specific serotonin reuptake inhibitor--SSRI) on active avoidance learning in fish. In an active, two-way, shuttle-box avoidance task we compared escape and avoidance of shock among fish receiving chronic administration of fluoxetine (Prozac), others receiving a 5-HT1A receptor antagonist (WAY 100,635; Sigma, St. Louis, MO) and controls. The receptor-blocked group performed significantly more Avoids than the fluoxetine group, which was lowest in performance, or than controls, which were slightly higher, and not significantly different from, the fluoxetine group. This conforms to results reported in rats. Active avoidance learning may be stimulated by the 5-HT1A receptor antagonist. Fluoxetine-treated fish seemed less active in their home tanks than controls or blocker-treated fish. These results suggest that at the dosages used in this experiment, the 5-HT1A receptor antagonist WAY 100,635 may have positive effects on cognition in fishes and its action may not necessarily be restricted to blockage of 5 HT reuptake inhibition. It seems that serotonin mechanisms may be highly conserved in vertebrate evolution. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pregnancy and risk of non-Hodgkin''s lymphoma: a prospective study

Glucose 6 phosphate dehydrogenase (G6PD) was estimated in the leucocytes of 35 patients with acute non-lymphocytic leukemia (ANLL) and 10 patients with chronic myeloid leukemia (CML). G6PD levels were found to be significantly decreased in majority of the patients with ANLL while it was increased in all CML patients. Variation in G6PD was found to be dependent on the percentage of myelocytes inANLL. Cytogenetic analysis was also carried out in these patients. Correlation analysis of leucocyte G6PD activity and karyotype with prognostic assessment clearly indicated the association of (s) high percentage of chromosomal abnormalities especially translocations, (b) low survival and remission rates, with patients having decreased G6PD activity when compared to patients with normal activity in ANLL. The studies indicate that leucocyte G6PD may be useful as a diagnostic and prognostic tool.