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Fahr disease, also known as familial idiopathic basal ganglia calcification, is a rare neurodegenerative disorder, the etiology of which remains unknown. Given its various presentations, Fahr disease is presumed to be underdiagnosed and its prevalence underestimated. We present a case of Fahr disease that presented mainly with pure psychiatric symptoms. Isolated psychiatric symptoms without neurological manifestations are rarely seen in patients diagnosed with Fahr disease. Psychiatrists should consider Fahr disease as a differential diagnosis in the evaluation of psychiatric illness.

Objective: Although the reduced function of the cytochrome P450 2D6*10 (CYP2D6*10) allele is common among Asian populations, existing evidence does not support paroxetine therapy adjustments for patients who have the CYP2D6*10 allele. In this study, we attempted to evaluate the degree of the impact of different CYP2D6 genotypes on the pharmacokinetic (PK) variability of paroxetine in a Japanese population using a population PK approach., Methods: This retrospective study included 179 Japanese patients with major depressive disorder who were being treated with paroxetine. CYP2D6*1, *2, *5, *10, and *41 polymorphisms were observed. A total of 306 steady-state concentrations for paroxetine were collected from the patients. A nonlinear mixed-effects model identified the apparent Michaelis-Menten constant (Km) and the maximum velocity (Vmax) of paroxetine; the covariates included CYP2D6 genotypes, patient age, body weight, sex, and daily paroxetine dose., Results: The allele frequencies of CYP2D6*1, *2, *5, *10, and *41 were 39.4, 14.5, 4.5, 41.1, and 0.6%, respectively. There was no poor metabolizer who had two nonfunctional CYP2D6*5 alleles. A one-compartment model showed that the apparent Km value was decreased by 20.6% in patients with the CYP2D6*10/*10 genotype in comparison with the other CYP2D6 genotypes. Female sex also influenced the apparent Km values. No PK parameters were affected by the presence of one CYP2D6*5 allele., Conclusion: Unexpectedly, elimination was accelerated in individuals with the CYP2D6*10/*10 genotype. Our results show that the presence of one CYP2D6*5 allele or that of any CYP2D6*10 allele may have no major effect on paroxetine PKs in the steady state.

Antidepressants, including selective serotonin reuptake inhibitors, are commonly prescribed for the treatment of affective disorders such as anxiety and depression. The purpose of this study was to investigate the central effects of acute administration of paroxetine (PXT) combined with lipoic acid (LA) on various behavioral models in mice. Paroxetine (10 and 20 mg/kg), LA (100 mg/kg), or vehicle was administered, intraperitoneally, 30 minutes before the tests. The results showed that PXT (10 mg/kg) alone and in combination with LA increased locomotor activity. In the anxiety models studied, an anxiolytic effect was observed after the administration of LA and PXT. In the tail suspension test, PXT at both doses and in combination with LA caused a significant decrease in immobility time. These results indicate possible anxiolytic and antidepressant effects of LA associated with PXT. These data suggest that coadministration of LA and PXT may improve anxiolytic and antidepressant responses, and being more effective than each drug alone. However, further studies are necessary to investigate the mechanism by which antioxidants exert antidepressant or anxiolytic action.

Objective: To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) and a serotonin and norepinephrine reuptake inhibitor (SNRI) in the treatment of depression in Parkinson disease (PD)., Methods: A total of 115 subjects with PD were enrolled at 20 sites. Subjects were randomized to receive an SSRI (paroxetine; n = 42), an SNRI (venlafaxine extended release [XR]; n = 34), or placebo (n = 39). Subjects met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression, and scored >12 on the first 17 items of the Hamilton Rating Scale for Depression (HAM-D). Subjects were followed for 12 weeks (6-week dosage adjustment, 6-week maintenance). Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR. The primary outcome measure was change in the HAM-D score from baseline to week 12., Results: Treatment effects (relative to placebo), expressed as mean 12-week reductions in HAM-D score, were 6.2 points (97.5% confidence interval [CI] 2.2 to 10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5% CI 0.1 to 8.4, p = 0.02) in the venlafaxine XR group. No treatment effects were seen on motor function., Conclusions: Both paroxetine and venlafaxine XR significantly improved depression in subjects with PD. Both medications were generally safe and well tolerated and did not worsen motor function., Classification of Evidence: This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD.

Background: The effects of paroxetine coadministration on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, were studied in 14 Japanese patients with schizophrenia., Methods: The patients had been treated with aripiprazole (24 mg/d in 5 cases, 12 mg/d in 5 cases, and 6 mg/d in 4 cases) for at least 2 weeks. Paroxetine 10 mg/d was coadministered during the first week, and the dose was increased to 20 mg/d during the second week. Blood samples were taken 3 times, before the start of paroxetine and then 1 and 2 weeks after paroxetine coadministration. On the same days, the severity of illness and extrapyramidal adverse effects were evaluated by the clinical global impressions and the Drug-Induced Extra-Pyramidal Symptoms Scale, respectively. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection., Results: Plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole during coadministration of paroxetine 10 and 20 mg/d were significantly (P < 0.05) higher (1.5-fold and 1.7-fold; 1.4-fold and 1.5-fold) than those before paroxetine coadministration. Those values during coadministration of paroxetine 20 mg/d were also significantly (P < 0.05) higher (1.1-fold and 1.1-fold) than those during coadministration of paroxetine 10 mg/d. Plasma concentrations of dehydroaripiprazole were unchanged throughout the study period. The mean clinical global impression score was significantly (P < 0.05) higher during the paroxetine 10 mg/d than that before coadministration, whereas the Drug-Induced Extra-Pyramidal Symptoms Scale scores remained unchanged during the study., Conclusions: This study suggests that lower doses (10-20 mg/d) of paroxetine coadministration increase plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole.

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression and are also associated with an increased falls risk. However, the biological mechanism underlying accidental falls with SSRI intake has yet to be elucidated. The present experimental study was designed to investigate whether obstacle avoidance skills in long-term (>90 days), senior paroxetine users (61 ± 5.8 years) are affected during gait, simple and challenging postural balance tasks, as well as during manual reaction time tasks. The performance of the paroxetine users was compared with healthy group-matched controls (60 ± 4.8 years). The results demonstrated impaired postural balance in the paroxetine users, especially during one-legged stance or under various dual-task conditions. Although the deficit in one-legged stance could indicate vestibular involvement, this was deemed unlikely because performance of standing on compliant surface with closed eyes remained unaffected. Paroxetine use also failed to affect manual reaction times or obstacle avoidance performance. It is suggested that paroxetine affects attentional capacities particularly in conjunction with balance control. Compared with healthy seniors, long-term senior users of paroxetine seem to be at an increased risk of falling due to impairments in balance control, especially when attention has to be divided between 2 concurrent activities.

Selective serotonin reuptake inhibitors are thought to interact with serotonergic neurons and be effective for treatment of panic disorder. In the present study, the authors investigated an association between plasma concentrations of paroxetine in patients with panic disorder and clinical response to initial treatment with paroxetine. Subjects were 21 unrelated Japanese patients who fulfilled DSM-IV-TR criteria for a diagnosis of panic disorder (6 males, 15 females, mean age 35.9 +/- 11.3 years). Subjects were administered 10 mg/day of paroxetine for 2 weeks as initial treatment. Improvement of the symptoms of the disorder was assessed with the Panic and Agoraphobia Scale (PAS). In the range of plasma levels >20 ng/mL, none of the subjects showed the reduction ratio in PAS score >0.2. The subjects whose plasma concentrations of paroxetine were less than 20 ng/mL had a significantly higher mean reduction ratio in PAS score than the subjects whose plasma concentrations of paroxetine were >20 ng/mL. Multiple regression analysis showed that the plasma concentration of paroxetine was the only significant factor and accounted for 28.0% of the variability in the reduction ratio of PAS score of the subjects. The final model of correlation was: reduction ratio in PAS score = 0.423 - 0.009 x (plasma concentrations of paroxetine) (R = 0.529, P = 0.014, coefficient of determination (R2) = 0.280). Assuming that the reduction ratio in PAS score was 0.2 in the equation above, plasma concentration of paroxetine is calculated to be about 25 ng/mL, which is suggested to be the upper end of the therapeutic window for the initial phase of the treatment with paroxetine for panic disorder.

A recent in vitro study has shown that paroxetine is a substrate of P-glycoprotein. However, there was no in vivo information indicating the involvement of P-glycoprotein on the pharmacokinetics of paroxetine. The aim of this study was to examine the effects of itraconazole, a P-glycoprotein inhibitor, on the pharmacokinetics of paroxetine. Two 6 day courses of either 200 mg itraconazole daily or placebo with at least a 4 week washout period were conducted. Thirteen volunteers took a single oral 20 mg dose of paroxetine on day 6 of both courses. Plasma concentrations of paroxetine were monitored up to 48 hours after the dosing. Compared with placebo, itraconazole treatment significantly increased the peak plasma concentration (Cmax) of paroxetine by 1.3 fold (6.7 +/- 2.5 versus 9.0 +/- 3.3 ng/mL, P < 0.05) and the area under the plasma concentration-time curve from zero to 48 hours [AUC (0-48)] of paroxetine by 1.5 fold (137 +/- 73 versus 199 +/- 91 ng*h/mL, P < 0.01). Although elimination half-life differed significantly (16.1 +/- 3.4 versus 18.8 +/- 5.9 hours, P < 0.05), the alteration was small (1.1 fold). The present study demonstrated that the bioavailability of paroxetine was increased by itraconazole, suggesting a possible involvement of P-glycoprotein in the pharmacokinetics of paroxetine.

Background: Patients taking antidepressants are more likely to also be taking multiple medications, increasing the risk of adverse drug-drug interactions (DDIs). Because of substantial inhibition of one or more cytochrome P450 (CYP) enzymes at therapeutic doses, the selective serotonin reuptake inhibitors fluoxetine, fluvoxamine, and paroxetine have a higher risk of CYP-mediated DDIs than citalopram, escitalopram, and sertraline, which do not substantially inhibit any CYP enzyme., Methods: Prescribing patterns in 2,779 Veterans Affairs (VA) patients who had a prescription for an antidepressant in the preceding year and a current prescription for at least one systemically active drug were analyzed to determine 1) prevalence of drug combinations with potential to cause CYP-mediated DDIs, 2) frequency of combinations of fluoxetine, paroxetine, or sertraline with drugs whose metabolism is principally dependent on CYP 2D6, and 3) use of reduced doses of CYP 2D6 substrate/drugs with narrow therapeutic indices in patients on fluoxetine or paroxetine compared with sertraline., Results: In 2,779 patients, 55 pairs of drugs with the potential to cause CYP-mediated DDIs occurred in 300 patients (11%), but only 26 of the patients and 6 of the drug pairs were identified by the VA Drug Alert System. Of the 461 patients receiving fluoxetine and/or paroxetine, 39 (8%) were also receiving a CYP 2D6-model substrate/drug with a narrow therapeutic index, 14 (36%) of whom were receiving high enough doses to be at moderate to high risk of a serious DDI., Conclusions: VA patients on fluoxetine, paroxetine, and sertraline were equally likely to be on drugs whose metabolism is dependent on CYP 2D6, including drugs with narrow therapeutic indices. No differences were found in doses of tricyclic antidepressants (i.e., "victim" drugs), which have narrow therapeutic indices and serious dose-dependent toxicity, when co-prescribed with fluoxetine or paroxetine versus sertraline (i.e., "perpetrator" drugs), despite predictable differences in CYP 2D6-mediated clearance of these drugs.

A selective and sensitive reversed-phase HPLC method was developed for the determination of the antidepressant paroxetine in plasma. The method is based on the purple chromogen formed by a displacement reaction of paroxetine with 7,7,8,8-tetracyanoquinodimethane (TCNQ) in acetonitrile at 80 degrees C for 20 minutes. For the assay, the drug was extracted from 1 mL of plasma with chloroform and, after sample alkalinization, derivatized with TCNQ; then the reaction mixture was directly injected into a C18 column. Desipramine was used as internal standard. The mobile phase was acetonitrile-water (70:30) at a flow-rate of 1.0 mL/min, and the derivatives were eluted at 13.1 and 15.5 minutes for paroxetine and desipramine, respectively, and detected at 567 nm. Calibration curve was found linear over the range of 20-400 ng/mL, and the detection limit was 2 ng/mL at a signal-to-noise ratio of 3/1. Recoveries determined for 3 concentrations range between 81.3% and 88.1%. Intraday and interday relative standard deviation values were found to be within 3.8%-13.5% and 8.2%-14.6%, respectively. With this developed method, a pharmacokinetic study was performed for paroxetine.

Objectives: We sought to determine whether chronic administration of paroxetine and electroconvulsive shock (ECS), given separately or jointly, changes the proliferative response of T and B lymphocytes stimulated by mitogens and affect the production of nitric oxide (NO) by peritoneal macrophages., Methods: The experiment was conducted on male Wistar rats receiving treatment once daily for 12 consecutive days. Control animals were injected intraperitoneally (ip) with sterile distilled water (2 mL/kg) and were subjected to sham ECS. Paroxetine was administered ip in a dose of 10 mg/kg of body weight. ECS (150 mA, 50 Hz, 0.5 seconds) was delivered through ear clips. For combined treatment, paroxetine was given 30 minutes before ECS. The rats were killed 24 hours after the last treatment. Then, the proliferative response of splenocytes was induced by concanavalin A (Con A), lipopolysaccharide (LPS), or pokeweed mitogen and those of thymocytes by Con A and was later assessed by a standard [H]-thymidine incorporation assay. The spontaneous or induced (with LPS) NO synthesis in peritoneal macrophages was assessed as nitrite accumulation in 24-hour culture supernatants using the Griess reaction., Results: Only chronic treatment with ECS alone significantly increased the proliferative response of splenocytes to stimulation with Con A or LPS. The response of thymocytes was not changed in any group tested. Both the spontaneous NO synthesis and that induced with LPS in macrophages were significantly decreased only in rats receiving ECS., Conclusions: We suggest that the ECS-induced suppression of NO synthesis by macrophages, resulting from the noradrenergic component of ECS action, may be responsible for the enhanced proliferative response of lymphocytes. Our data are in line with the results of other authors indicating that paroxetine and/or ECS modulate the immune system indirectly via the neuroendocrine system. The relatively high efficacy of ECS in the therapy for depression may be attributable to the ECS-evoked long-lasting changes in the immune system, which supports the macrophage theory of depression.

Summary: The effects of paroxetine on steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) were studied in 10 patients with schizophrenia or schizoaffective disorder. Patients stabilized using risperidone therapy (4-8 mg/d) also received paroxetine (20 mg/d) for 4 weeks. During paroxetine administration, mean plasma concentrations of risperidone increased significantly (P < 0.01), whereas levels of 9-OH-risperidone decreased slightly but not significantly. After 4 weeks of paroxetine treatment, the sum of the concentrations of risperidone and 9-OH-risperidone (active moiety) increased significantly by 45% (P < 0.05) over baseline. The mean plasma risperidone/9-OH-risperidone ratio was also significantly modified (P < 0.001) during paroxetine treatment. The drug combination was generally well tolerated with the exception of one patient who developed Parkinsonian symptoms in the second week of adjunctive therapy. In this patient total plasma levels of risperidone and its active metabolite increased by 62% during paroxetine co-administration. The authors' findings indicate that paroxetine, a potent inhibitor of CYP2D6, may impair the elimination of risperidone, primarily by inhibiting CYP2D6-mediated 9-hydroxylation and to a lesser extent by simultaneously affecting the further metabolism of 9-OH-risperidone or other pathways of risperidone biotransformation. Careful clinical observation and possibly monitoring of plasma risperidone levels may be useful whenever paroxetine is co-administered with risperidone.

Background: There is increasing evidence that serotonergic neurotransmission may be damaged in poststroke pathological crying. A correlation between the clinical severity of pathological crying and the size of stroke-induced serotonergic pathway lesions is commonly accepted. We present a case of severe pathological crying after a limited left anterior choroidal artery territory infarction., Case Description: A right-handed 55-year-old man who was a heavy smoker was admitted to the hospital after a right hemiplegia of sudden onset. Clinical examination revealed a right global hemiplegia including the face and a right hemihypoesthesia. Cerebral CT scan and MRI showed an infarct in the retrolenticular part of the posterior limb of the left internal capsule extending upward into the posterior paraventricular corona radiata region. Transesophageal echocardiography revealed an atrial septal aneurysm of 15-mm excursion without associated patent foramen ovale. From the first day of admission, the patient exhibited very frequent and intense fits of pathological crying. Their persistence led to initiation of treatment with the selective serotonin reuptake inhibitor paroxetine on day 30. Complete and immediate resolution of pathological crying occurred 24 hours after onset of therapy. Follow-up examination at day 90 confirmed the absence of relapse of pathological crying., Conclusions: We conclude that poststroke pathological crying in our patient may have been due to unilateral disruption of the capsular ascending projections of the serotonergic brain stem raphe nuclei. A small left-sided capsular lesion may have led to severe pathological crying. This disabling condition may be reversible with selective serotonin reuptake inhibitor therapy.