Paroxetine and galactorrhea

The authors report a case of galactorrhea following antidepressant treatment where paroxetine might be responsible. Paroxetine is a selective serotonergic reuptake inhibitor (SSRI). Galactorrhea occasionally is a dopamine-mediated side effect observed with neuroleptic drugs. However, the ability to produce extrapyramidal side effects is known for tricyclic as well as for SSRIs. Thus the potential of SSRIs to induce dopamine-dependent side effects is a clinical reality and it was not surprising to observe galactorrhea due to paroxetine. However, in a review of the literature no reported cases of galactorrhea associated with paroxetine were found.     

Prophylactic antiemetic therapy with granisetron-droperidol combination in patients undergoing laparoscopic cholecystectomy

Paroxetine (Paxil) is a selective serotonin reuptake inhibitor, one of a new class of antidepressants used in the treatment of obsessive-compulsive disorder, panic disorder, and depression. Paroxetine potentiates serotonergic activity through the selective inhibition of serotonin reuptake in the central nervous system. There are few reported overdoses in the literature, and of these, three were fatal. Three coroner's cases in which paroxetine was directly associated with the cause of death are reported. In case #1, paroxetine was the only drug detected in significant concentrations. The heart blood paroxetine concentration was 4.0 mg/L. Case #2 was a known suicide in which the decedent herself admitted taking pills and alcohol. The hospital blood sample drawn at admission was analyzed and contained a 0.25% ethanol level and no paroxetine. Death occurred 10 h later. The postmortem heart blood contained ethanol at 0.06%, paroxetine at 3.7 mg/L, fluoxetine at 0.86 mg/L, and norfluoxetine at 0.65 mg/L. In case #3, death was attributed to an apparent adverse drug interaction between paroxetine and imipramine/desipramine. The postmortem heart blood contained paroxetine at 1.4 mg/L, imipramine at 3.0 mg/L, and desipramine at 9.6 mg/L.     

Serum anticholinergicity in elderly depressed patients treated with paroxetine or nortriptyline

OBJECTIVE: The authors' goal was to compare serum anticholinergicity of 61 elderly depressed patients randomly assigned to double-blind treatment with paroxetine (N=31) or nortriptyline (N=30). METHOD: Both antidepressants were titrated in a standardized manner, and plasma was sampled weekly for measurement of paroxetine and nortriptyline and its hydroxy metabolite concentrations. Serum anticholinergicity was measured at baseline and after 1, 4, and 6 weeks of treatment. Side effects were assessed by using a validated scale. RESULTS: After correcting for pretreatment anticholinergicity, the authors found that mean serum anticholinergicity for the nortriptyline-treated patients was significantly greater than that for the paroxetine group at all weeks assessed. Serum anticholinergicity was significantly correlated with nortriptyline but not with paroxetine plasma levels. Complaints of dry mouth and tachycardia were significantly more frequent and severe in the nortriptyline group. CONCLUSIONS: These findings suggest that, at therapeutic plasma concentrations, paroxetine has approximately one-fifth the anticholinergic potential of nortriptyline in older patients.     

Enhancement of morphine antinociception by ibogaine and noribogaine in morphine-tolerant mice

BACKGROUND: The authors evaluated and compared the efficacy of 20 mg versus 40 mg of paroxetine in a randomized, double-blind, parallel-group study during a maintenance period of 28 months. METHOD: Ninety-nine inpatients with recurrent, unipolar depression (DSM-IV criteria) who had at least 1 depressive episode during the 18 months preceding the index episode were openly treated with paroxetine 40 mg/day. Seventy-two subjects had a stable response (Hamilton Rating Scale for Depression score < 8) to paroxetine treatment and remained in the continuation treatment as outpatients for 4 months. At the time of recovery, 68 patients were randomly assigned to 1 of the 2 maintenance treatment groups: paroxetine 20 mg or paroxetine 40 mg daily. RESULTS: Sixty-seven patients completed the 28-month follow-up period. Seventeen (51.5%) of 33 patients in the 20-mg paroxetine regimen had a single recurrence compared with 8 (23.5%) of 34 subjects in the 40-mg dose regimen (chi2 = 5.56, p = .018). CONCLUSION: These data suggest that a full dose of paroxetine is recommended in unipolar patients who are at high risk for recurrent depressive episodes.     

Nocturnal hemodialysis (NHD) adapted to the in-centre setting--a pilot study

The authors report on a 42-year-old female inpatient with bipolar I disorder, whose dysphoric mania responded rapidly and completely while her antimanic medication (lithium, carbamazepine, clozapine, haloperidol and clonazepam) was supplemented by 20 mg of paroxetine daily. The practical and theoretical importance of this case is briefly discussed.     

Determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition by paroxetine and fluvoxamine in vivo

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.     

Nicotine patch and paroxetine for smoking cessation.

Smokers (N?=?224) were randomized to 1 of 3 groups: (a) transdermal system (TNS) + placebo; (b) TNS + paroxetine (20 mg); (c) TNS + paroxetine (40 mg). Assignment to treatment was double-blind. Nicotine patch (TNS) treatment was provided for 8 weeks; paroxetine or placebo was provided for 9 weeks. Abstinence rates at Weeks 4, 10, and 26 were as follows: (a) TNS + placebo: 45%, 36%, and 25%; (b) TNS + paroxetine (20 mg): 48%, 33%, and 21 %; (c) TNS + paroxetine (40 mg): 57%, 39%, and 27%. The differences were not statistically significant. The combined treatment was more effective in reducing both craving and depression symptoms associated with smoking cessation. A subgroup analysis comparing compliant participants was also conducted. Abstinence rates at Weeks 4, 10, and 26 were as follows: (a) TNS + placebo: 46%, 35%, and 24%; (b) TNS + paroxetine (20 mg): 64%, 43%, and 33%; (c) TNS + paroxetine (40 mg): 74%, 51%, and 38%. The differences between paroxetine groups and placebo at Week 4 were statistically significant. Although paroxetine may add value to the current standard of care in excess of potential risk, more conclusive evidence is needed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients

The authors analyzed the incidence of sexual dysfunction (SD) with different selective serotonin reuptake inhibitors (SSRIs; fluoxetine, fluvoxamine, paroxetine, and sertraline) and hence the qualitative and quantitative changes in SD throughout time in a prospective and multicenter study. Outpatients (192 women and 152 men; age = 39.6 +/- 11.4 years) under treatment with SSRIs were interviewed with an SD questionnaire designed for this purpose by the authors and that included questions about the following: decreased libido, delayed orgasm or anorgasmia, delayed ejaculation, inability to ejaculate, impotence, and general sexual satisfaction. Patients with the following criteria were included: normal sexual function before SSRI intake, exclusive treatment with SSRIs or treatment associated with benzodiazepines, previous heterosexual or self-erotic current sexual practices. Excluded were patients with previous sexual dysfunction, association of SSRIs with neuroleptics, recent hormone intake, and significant medical illnesses. There was a significant increase in the incidence of SD when physicians asked the patients direct questions (58%) versus when SD was spontaneously reported (14%). There were some significant differences among different SSRIs: paroxetine provoked more delay of orgasm or ejaculation and more impotence than fluvoxamine, fluoxetine and sertraline (chi 2, p < .05). Only 24.5% of the patients had a good tolerance of their sexual dysfunction. Twelve male patients who suffered from premature ejaculation before the treatment preferred to maintain delayed ejaculation, and their sexual satisfaction, and that of their partners, clearly improved. Sexual dysfunction was positively correlated with dose. Patients experienced substantial improvement in sexual function when the dose was diminished or the drug was withdrawn. Men showed more incidence of sexual dysfunction than women, but women's sexual dysfunction was more intense than men's. In only 5.8% of patients, the dysfunction disappeared completely within 6 months, but 81.4% showed no improvement at all by the end of this period. Twelve of 15 patients experienced total improvement when the treatment was changed to moclobemide (450-600 mg/day), and 3 of 5 patients improved when treatment was changed to amineptine (200 mg/day).     

Heart rate variability in depressed patients and differential effects of paroxetine and amitriptyline on cardiovascular autonomic functions

Twenty-four unmedicated patients with episodes of major depression (DSM-III-R) and an age- and sex-matched group of 24 normal subjects underwent a heart rate analysis. The battery of cardiovascular reflex tests included the coefficient of variation while resting (CVr) and during deep breathing (CVdr), a spectral analysis of heart rate variability, the Valsalva test, and the posture index. The depressed patients showed no significant abnormalities in any of the tests as compared to the healthy subjects. The 24 patients were randomly allocated for treatment with either amitriptyline or paroxetine. During treatment with 20 mg paroxetine per day, patients showed no changes in cardiovascular autonomic function tests after 14 days. However, treatment with 150 mg amitriptyline per day decreased all heart rate parameters significantly due to anticholinergic side effects, except heart rate, which increased significantly. As autonomic side effects are a potential hazard of antidepressant therapy, the data suggest that paroxetine is an appropriate antidepressant for cases with pre-existing cardiovascular autonomic neuropathy.     

Response styles among patients with minor depression and dysthymia in primary care.

Ruminative responses to depression have predicted duration and severity of depressive symptoms. The authors examined how response styles change over the course of treatment for depression and as a function of type of treatment. They also examined the ability of response styles to predict treatment outcome and status at follow-up. Primary care patients (n=96) with dysthymia or minor depression were randomly assigned to problem-solving therapy, paroxetine, or placebo. Patients' depressive symptoms and rumination, but not distraction, decreased over time. Pretreatment rumination and distraction were associated with more depressive symptoms at the conclusion of treatment; the latter finding was not consistent with the response style theory of depression. Results are discussed in terms of their implications for this theory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of fludarabine on pharmacokinetics and pharmacodynamics of cytarabine: implications for a continuous infusion schedule

The selective serotonin reuptake inhibitor, paroxetine, has been reported to inhibit cytochrome P450 activity. Nitric oxide synthase (NOS) is structurally homologous to cytochrome P450. Accordingly, in our study, we observed the effects of paroxetine on NOS activity. Seventeen ischemic heart disease (IHD) patients received paroxetine and fourteen received nortriptyline for treatment of clinical depression defined by a score of 17 or higher on the Hamilton Rating Scale for Depression (HAM-D). Serum nitrite and nitrate levels were significantly decreased following paroxetine treatment but not nortriptyline treatment. Paroxetine was also a more potent inhibitor of NOS enzyme activity than nortriptyline, as measured by the conversion of [14C] arginine to [14C] citrulline by hamster brain cytosols. In addition, paroxetine reversed the force-frequency relationship in isolated hamster papillary muscles in a manner analogous to that of known NOS inhibitors. Thus, paroxetine appears to be a novel NOS inhibitor in vitro and in vivo.     

With reference to: RAYS 21,3,1996 venous thromboembolism

This study evaluated paroxetine as a possible treatment for premature ejaculation. Sixty two patients affected by primary premature ejaculation were randomly assigned to two groups. A and B, and treated with two different treatment schedules. Patients assigned to group A were treated with paroxetine 20 mg p.o. daily for six months; patients assigned to group B were treated with paroxetine 20 mg p.o. daily for fourteen days, and than dose was reduced to 10 mg for a total treatment period of six months. Only one patient reported significative side effects (weakness). Positive clinical results were obtained, at the end of the treatment, in 89 per cent of group A and 88 per cent of group B. In patients with primary premature ejaculation, paroxetine represents, in our opinion, the best therapeutic option for its efficacy and lack of significant side effects.     

Sociocultural influences and care of dying children in Japan and the United States

Depression is a common cause of sexual dysfunction, but also antidepressant medication is often associated with sexual side effects. This article includes two related studies. The first double-blind, placebo-controlled study was conducted in men with lifelong rapid ejaculation and aimed to assess putative differences between the major selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine, and sertraline) with regard to their ejaculation-delaying effect. Sixty men with an intravaginal ejaculation latency time (IELT) of 1 minute or less were randomly assigned to receive fluoxetine 20 mg/day, fluvoxamine 100 mg/day, paroxetine 20 mg/day, sertraline 50 mg/day, or placebo for 6 weeks. During the 1-month baseline and 6-week treatment periods, the men measured their IELT at home using a stopwatch. The trial was completed by 51 men. During the 6-week treatment period, the geometric mean IELT in the placebo group was constant at approximately 20 seconds. Analysis of variance revealed a between-groups difference in the evolution of IELT delay (p = 0.0004); in the paroxetine, fluoxetine, and sertraline groups there was a gradual increase to about 110 seconds, whereas in the fluvoxamine group, IELT was increased to only approximately 40 seconds. The paroxetine, fluoxetine, and sertraline groups differed significantly (p < 0.001, p < 0.001, p = 0.017, respectively) from placebo but the fluvoxamine group did not (p = 0.38). Compared with baseline, paroxetine exerted the strongest delay in ejaculation, followed by fluoxetine and sertraline. There was no clinically relevant delay in ejaculation with fluvoxamine. In men with lifelong rapid ejaculation, paroxetine delayed ejaculation most strongly, whereas fluvoxamine delayed ejaculation the least. The second double-blind, placebo-controlled study was carried out in men with lifelong rapid ejaculation (IELT < or = 1 minute) and in men with lifelong less-rapid ejaculation (IELT > 1 minute) to investigate whether data about SSRI-induced delayed ejaculation in men with rapid ejaculation may be extrapolated to men with less-rapid ejaculation. After measurement of IELT at home (using a stopwatch) during a 1-month baseline assessment, 32 men with an IELT of 1 minute or less (group 1) or more than 1 minute (group 2) were randomly assigned to receive paroxetine 20 mg/day or placebo for 6 weeks in a double-blind manner. Patients continued to measure their IELTs at home during the 6 weeks of the study. At baseline, 24 patients consistently had IELTs of one minute or less (group 1), and eight patients had IELTs of more than 1 minute (group 2). The geometric mean IELT was 14 seconds in group 1 and 83 seconds in group 2. Twelve patients in group 1 and five in group 2 were randomized to the paroxetine 20 mg/day. The percentage increase in the geometric mean IELT compared with baseline in patients treated with paroxetine was 420% (95% confidence interval [CI], 216-758%) in group 1 and 480% (95% CI, 177-1,118%) in group 2 (p = 0.81). After 6 weeks of treatment with paroxetine, the geometric mean IELT was 92 seconds in group 1 and 602 seconds in group 2 (p < 0.001). Therefore, the paroxetine-induced percentage increase in IELT seems to be independent of the baseline IELT. This suggests that ejaculation-delaying side effects of some SSRIs investigated in men with lifelong rapid ejaculation may be generalized to men with less-rapid ejaculation.     

Paroxetine. A review of its pharmacology, therapeutic use in depression and therapeutic potential in diabetic neuropathy

Paroxetine is a selective serotonin reuptake inhibitor effective in a once-daily administration regimen in the treatment of depression. In elderly patients (aged > or = 60 years) with major depression, short term (6 weeks) treatment with paroxetine produces clinical improvements significantly superior to those seen with placebo and similar to those with tricyclic antidepressant agents, mianserin and fluoxetine. There is evidence that paroxetine has positive effects on co-existing anxiety and does not precipitate agitation. Paroxetine has also shown potential in the symptomatic treatment of diabetic neuropathy; however, further clinical experience is needed to confirm this preliminary result. Short term paroxetine therapy is associated with fewer anticholinergic and CNS adverse effects, but generally more gastrointestinal disturbances, than tricyclic antidepressants and mianserin. Unlike the tricyclic agents, paroxetine does not significantly affect cardiovascular function or impair psychomotor performance. This tolerability profile should be particularly beneficial in elderly patients, who are generally more susceptible than younger patients to the anticholinergic and CNS adverse events associated with tricyclic antidepressant drugs, and in whom there is a higher prevalence of pre-existing cardiovascular disease. It also suggests an important potential advantage over tricyclic antidepressants in the setting of overdosage. Thus, primarily because of its better tolerability profile and potentially lower toxicity in overdosage and in patients with cardiovascular disease, paroxetine appears to be a more attractive option than tricyclic antidepressants for the treatment of depression in late life. Future research should attempt to define more fully the efficacy of paroxetine as long term prophylactic therapy for recurrent depression and to assess how its overall therapeutic profile compares with other selective serotonin reuptake inhibitors in the elderly.     

Infiltrative basal cell carcinoma occurring in sites of biopsy-proven nodular basal cell carcinoma

OBJECTIVE: The authors studied factors associated with short-term treatment response in 38 nondepressed subjects with DSM-III-R obsessive-compulsive disorder (OCD). METHOD: The subjects completed 12 weeks of treatment with paroxetine (N = 20), placebo (N = 8), or cognitive-behavioral therapy (N = 10). Clinician and self-rated measures were gathered at baseline, during treatment, and after treatment. RESULTS: Seventeen (45%) subjects had "much" or "very much" improvement and achieved at least a 40% decrease in their total Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score. Responders had lower obsessive-compulsive scores on the Symptom Checklist 90-Revised, had a lower checking score on the Maudsley Obsessive-Compulsive Inventory, were less likely to have had prior drug therapy, and in general suffered more obsessive-compulsive symptoms. They were significantly less likely to have hoarding obsessions and corresponding compulsions. The latter finding was confirmed using multiple regression analysis. CONCLUSION: Hoarding is an important symptom that predicts poor treatment response in patients with OCD.     

High affinity [3H]imipramine and [3H]paroxetine binding sites in suicide brains

Specific binding of [3H]imipramine and [3H]paroxetine was simultaneously examined in human brains (frontal cortex, temporal cortex, cingulate cortex, hypothalamus, hippocampus and amygdala) from 11 controls and 11 depressed suicide victims. A single saturable high affinity site was obtained for both radioligands. Age was not related to significant changes in [3H]imipramine and [3H]paroxetine binding parameters, which indicates the stability of the brain serotonergic system with increasing age. A major finding of the present study concerns the existence of a significant decrease in the maximum number (Bmax) of [3H]imipramine binding sites in hippocampus from depressed suicides as compared with the control group, without changes in the binding affinity (Kd). In contrast, when [3H]paroxetine was used as radioligand, no changes in either Bmax or Kd were detected in any of the brain regions studied. These findings suggest that [3H]imipramine may be a better marker than [3H]paroxetine when alterations in the presynaptic serotonergic uptake site are to be detected.     

Therapeutic endoscopy of the hepatobiliary and pancreatic system: a Vietnamese experience

We studied the effect of the selective serotonin reuptake inhibitor (SSRI), paroxetine, on basal plasma prolactin concentrations in 11 healthy subjects. Subjects were tested before paroxetine, and after 1 and 3 weeks of treatment (20 mg daily). On each test occasion prolactin levels were sampled before and following administration of a placebo capsule, for a total of 4 h. After 3 weeks paroxetine treatment plasma prolactin levels were significantly higher than those seen either pre-treatment or after 1 week of treatment. In contrast, 1 week of paroxetine treatment did not significantly increase prolactin concentrations over pre-treatment values. Plasma concentrations of paroxetine did not differ between 1 and 3 weeks of treatment. The secretion of plasma prolactin is, in part, under the tonic regulation of serotonergic pathways and the present results therefore support animal experimental data suggesting that SSRIs produce a delayed increase in some aspects of brain serotonin neurotransmission.     

Antidepressant pharmacotherapy: economic evaluation of fluoxetine, paroxetine and sertraline in a health maintenance organization

The present study was designed to compare direct health service expenditures, for the treatment of depression, among patients enrolled in a health maintenance organization, and prescribed one of three selective serotonin reuptake inhibitors, fluoxetine, paroxetine or sertraline. Information regarding depression-related health service use was derived from the computer archive of a network-model health maintenance organization system serving 700,000 beneficiaries. A total of 744 health maintenance organization beneficiaries were found to satisfy the study selection criteria. Multivariate regression analysis was used to determine the incremental influence of selected demographic, clinical, financial and provider characteristics on health service expenditures related to the treatment of depression (ICD-9-CM, or DSM-IV code 296.2) 1 year after the start of antidepressant pharmacotherapy. Multivariate findings indicate that treatment with paroxetine increases average expenditures for physician visits ($31.93; P < or = 0.05), psychiatric visits ($19.33; NS), laboratory tests ($2.35; P < or = 0.05), hospitalizations ($85.33; P < or = 0.05), psychiatric hospitalizations ($82.01; P < or = 0.05), and antidepressant pharmacotherapy ($63.72; P < or = 0.05), for a total per capita increase in health service use of $284.68 (P < or = 0.05), compared with treatment with fluoxetine. Sertraline treatment increases average expenditures for physician visits ($21.74; P < or = 0.05), psychiatric visits ($56.79; P < or = 0.05), laboratory tests ($1.21; P < or = 0.05), hospitalizations ($70.59; P < or = 0.05), psychiatric hospitalizations ($95.75; P < or = 0.05), and antidepressant pharmacotherapy ($69.85; P < or = 0.05), for a total per capita increase in health service use of $315.96 (P < or = 0.05), compared with treatment with fluoxetine. Economic comparisons between paroxetine and sertraline did not demonstrate any significant differences in expenditures for the health services examined.     

Evaluation of iatrogenic accessory nerve injury in forensic medical practice

The authors give a survey of the clinical and medical-legal characteristics of the accessory nerve injury. In the past two decades the conception of the successfulness of the surgical treatment of the accessory nerve injury became prevailing. About the medical-legal aspects of the iatrogenic injury of the nerve reported in connection of the reconstructive surgery chiefly also departments of neurosurgery, orthopedics and traumatology. In the case of the authors a 70 year old patient suffered 10 years ago a iatrogenic accessory nerve injury. The mild trapezius palsy recovered spontaneously practically with cosmetic disadvantage. In connection with the development of extreme dorso-lumbal scoliosis associated with torsion the trapezius atrophy worsened. Physical therapy was partly successful. But the patient became unfit for manual work. Their observations sustain the data of authors who established that in the case of accessory nerve injury not only the surgical but also conservative treatment is usually successful. In opposite to certain data of the literature the authors establish that the iatrogenic injuries of the accessory nerve may lead to significant lifelong disability. The diagnosis is not always made in time with consequent delay in repair. This may be regarded as an unfavorable issue during medical-legal discussions. The authors recommend in interest to prevent nerve injury in the posterior triangle of the neck to perform operation in special department.     

Diagnostic pearls in the management of vitreomacular disorders

Pharmacokinetic interactions of clozapine and its metabolites N-desmethylclozapine and clozapine N-oxide with the selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and paroxetine were investigated in a prospective study in schizophrenic patients under steady-state conditions. Thirty patients were treated with clozapine at a target dose of 2.5 to 3.0 mg/kg of body weight. After gradual dose escalation, serum concentrations of clozapine and two metabolites were determined twice at 7-day intervals after steady-state conditions had been reached. Then, fluvoxamine (50 mg/day) or paroxetine (20 mg/day) was added in 16 and 14 patients, respectively. Serum concentrations of clozapine and its metabolites were measured after 1, 7, and 14 days of coadministration with the SSRI. Mean trough concentrations of steady-state serum concentrations of clozapine, N-desmethylclozapine, and clozapine N-oxide were markedly elevated under fluvoxamine by about threefold of baseline concentrations whereas paroxetine induced only minor, nonsignificant changes. Estimation of the mean elimination half-life of clozapine 2 weeks after start of fluvoxamine comedication revealed an increase from 17 hours to about 50 hours whereas there was no change under paroxetine coadministration. The N-desmethylclozapine/clozapine ratio did not change significantly with either SSRI. Under monotherapy, clozapine mean serum concentrations in smokers were significantly lower by 32% compared with nonsmokers. Similarly, N-demethylation ratios were about 20 to 50% higher in smokers. Thus, in all patients, fluvoxamine induced relevant increases in serum concentrations of clozapine and its metabolites, probably by the inhibition of enzymes catalyzing the degradation of clozapine and N-desmethylclozapine, whereas paroxetine, at a usual clinically effective dosage of 20 mg/day, did not cause significant pharmacokinetic interactions.