fluvoxamine and Schizophrenia

The four Ds of medical malpractice are duty, dereliction (negligence or deviation from the standard of care), damages, and direct cause. Each of these four elements must be proved to have been present, based on a preponderance of the evidence, for malpractice to be found. The principles of psychopharmacology and the information in the package insert for a drug often play a central role in deciding whether dereliction and direct cause for damages were or were not applicable in a particular case. The author uses data from two cases in which patients were inadvertently fatally poisoned by medication to illustrate two ways in which such information can affect the outcome. In one case, the clinician should have known that he was giving a toxic dose to the patient, whereas that was not true in the other case.

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Child; Depressive Disorder; Desipramine; Fatal Outcome; Female; Fluvoxamine; Forensic Psychiatry; Humans; Imipramine; Male; Malpractice; Mental Disorders; Psychopharmacology; Schizophrenia; Thioridazine

The addition of fluvoxamine to clozapine induces a rise of plasma concentrations of clozapine. This enables the prescription of a lower number of clozapine tablets, yet it attains sufficient clozapine plasma concentrations, and facilitates treatment adherence.. Providing practical advice for the practical implementation of the addition of fluvoxamine to clozapine.. A review of the literature with Ovid Medline and the presentation of a case series (N=7).. Addition of 25 or 50 mg fluvoxamine induces a mean rise of plasma concentrations of clozapine with a factor 2-3, probably even higher with the addition of 100 mg. However, the range of this factor varies considerably between individuals. The use of clozapine and fluvoxamine at the same time possibly has a favourable impact on the metabolic side-effects of clozapine.. Addition of fluvoxamine to clozapine can lead to a dangerous rise of clozapine plasma concentrations. However, it can also be used to prescribe a lower number of clozapine tablets and to facilitate treatment adherence. A sufficient safety margin should be taken and regular control of clozapine plasma concentrations is mandatory.

Topics: Antipsychotic Agents; Clozapine; Drug Interactions; Drug Synergism; Fluvoxamine; Humans; Schizophrenia

We performed an updated meta-analysis of fluvoxamine add-on therapy in patients with schizophrenia treated with antipsychotics based on two previous meta-analyses (Sepehry et al., in J Clin Psychiatry 68:604-610, 2007 and Singh et al., in Br J Psychiatry J Mental Sci 197:174-179, 2010). We searched PubMed, the Cochrane Library database, and PsycINFO up to January 2013. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing fluvoxamine add-on therapy with placebo. The risk ratio (RR), 95 % confidence intervals (CI), and standardized mean difference (SMD) were calculated. Seven studies (total n = 272) were identified. These included two clozapine studies, one olanzapine study, one second-generation antipsychotic (SGA) monotherapy study, and three first-generation antipsychotics (FGAs) monotherapy studies. There were significant effect of fluvoxamine add-on therapy on overall (SMD = -0.46, CI = -0.75 to -0.16, p = 0.003, I (2) = 0 %, 5 studies, n = 180) and negative symptoms (SMD = -0.44, CI = -0.74 to -0.14, p = 0.004, I (2) = 0 %, 5 studies, n = 180). However, fluvoxamine add-on therapy showed no significant effects on positive symptoms, depressive symptoms, and discontinuations from any cause or adverse events. Fluvoxamine add-on therapy in patients primarily treated with SGAs improved overall (p = 0.02) but not negative symptoms (p = 0.31). On the other hand, fluvoxamine add-on therapy in patients primarily treated with FGAs improved both overall (p = 0.04) and negative symptoms (p = 0.004) compared with control groups. Our results suggest that fluvoxamine add-on therapy is more beneficial on the psychopathology (especially negative symptoms) than controls in patients with schizophrenia who are primarily treated with FGAs. Given that a small number of studies were included in this meta-analysis, the results should be treated with caution.

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Databases, Factual; Fluvoxamine; Humans; Middle Aged; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Topics: Affect; Analysis of Variance; Antipsychotic Agents; Drug Therapy, Combination; Fluvoxamine; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Selective Serotonin Reuptake Inhibitors; Time Factors; Treatment Outcome

When predicting the effects of medication for psychiatric diseases and their side effects based on genetic information, there are many things to consider besides just genetic information, including the index to be evaluated. We have shown before that it is important to simultaneously analyze both pharmacokinetic factors such as the blood concentration and pharmacodynamic factors such as the site of drug action, when searching for genetic information that can be used to predict the treatment effects of fluvoxamine for depression and its side effects. For example, we have shown that there exists a specific concentration that can be used to predict remission in the treatment of depression with fluvoxamine (Fukui et al, 2008); however, it is considered that without a sufficient examination of such factors besides genetic information, it is difficult to predict the effects using just genetic information. On the other hand, the situation is more complex with medication for schizophrenia. Although it appears that consensus has been obtained in that the goal of medication for depression is remission, the goal of medication for schizophrenia is not clear and it cannot be said that prediction studies on the effects have been sufficiently conducted using genetic information. Therefore, at our facility, focusing on metabolic anomalies due to antipsychotics, QT prolongation, and hyperprolactinemia, which have become issues in recent years, a prediction study on side effects was conducted. Because such side effects can be quantified, in comparison with the effects study, it is advantageously simple to examine the relationship with genetic information. However, in the course of this study, we discovered that there was a gender difference in terms of glycolipid metabolic anomalies, that antipsychotics particularly extended the QT interval during nighttime, and that prolactine following the administration of antipsychotics temporally increased before declining again a few weeks later. We believe that when examining the relationship between side effects and genetic information, the genetic information may not be sufficiently utilized unless the analysis is performed after obtaining a better understanding of the characteristics of such side effects.

Topics: Adult; Antidepressive Agents, Second-Generation; Female; Fluvoxamine; Glycolipids; Humans; Hyperprolactinemia; Long QT Syndrome; Male; Metabolic Syndrome; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Precision Medicine; Receptors, Dopamine D2; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Young Adult

In the past decade there has been increasing interest in the potential benefit of early pharmacological intervention in schizophrenia. Patients with schizophrenia show nonpsychotic and nonspecific prodromal symptoms (e.g., depression and cognitive deficits) for several years preceding the onset of frank psychosis. Several studies have demonstrated that medication with atypical antipsychotic drugs in people with prodromal symptoms may reduce the risk of subsequent transition to schizophrenia. Furthermore, a naturalistic treatment study in young people with prodromal symptoms demonstrated that medication with antidepressants could prevent the development of psychosis. Although the sample in this study was small, the results were striking. Some antidepressants, including selective serotonin reuptake inhibitors (SSRIs), had high to moderate affinities at the endoplasmic reticulum protein sigma-1 receptors, which are implicated in neuroprotection and neuronal plasticity. Among all antidepressants, fluvoxamine was the most potent sigma-1 receptor agonist. Since the effects of fluroxaming were antagonized by the selective sigma-1 receptor antagonist NE-100. Based on the role of sigma-1 receptors in the pathophysiology of cognition and depression, the author would like to propose a hypothesis that SSRIs (e.g., fluvoxamine) with sigma-1 receptor agonism may reduce the risk of subsequent transition to schizophrenia.

Topics: Animals; Antipsychotic Agents; Fluvoxamine; Humans; Receptors, sigma; Schizophrenia; Sigma-1 Receptor

Negative symptoms are core features of schizophrenia that respond poorly to first-generation antipsychotics and present a major obstacle in rehabilitation. Patients may be somewhat more responsive to clozapine and second-generation antipsychotics but even then, considerable impairment remains. This paper reviews the use of selective serotonin re-uptake inhibitor (SSRI) augmentation of antipsychotics in the treatment of negative symptoms in schizophrenia. Important methodological issues particular to the study of negative symptoms are also discussed. Current evidence indicates that at least two SSRIs, fluvoxamine and fluoxetine, can ameliorate primary negative symptoms in chronic schizophrenic patients treated with first-generation antipsychotics. Onset of improvement may be detected within 2 weeks of starting treatment. The combination is well-tolerated, although as antipsychotic drug concentrations may rise, close monitoring of drug doses and possibly drug concentrations is needed. So far, evidence regarding SSRI augmentation of second-generation antipsychotics is limited and in view of the increasing use of these newer agents, controlled studies are urgently needed. SSRI augmentation may be a useful addition to the treatment of schizophrenic patients with persistent negative symptoms. The paradoxical findings that both clozapine, a serotonin antagonist, and an SSRI antidepressant added to antipsychotics, can improve negative symptoms suggests that these pharmacologically distinct treatments may share common final mechanisms. A better understanding of these mechanisms can shed light on the pathogenesis of negative symptoms and provide new targets for drug development.

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Chemotherapy, Adjuvant; Fluoxetine; Fluvoxamine; Humans; Schizophrenia; Schizophrenic Psychology; Selective Serotonin Reuptake Inhibitors

Obsessive-compulsive disorder (OCD) is characterized by obsessions, compulsions, or both, which cause significant personal distress or social dysfunction. OCD is a common psychiatric illness with a prevalence of 1-2%. Because most people have regular contact with primary health care services, the patient with OCD is likely to see their general practitioner even though psychological problems may not be the main reason for consultation. Early recognition of the disorder facilitates early intervention. This reduces distress, disability and burden of illness. Pharmacological treatment with serotonin reuptake inhibitors (SRI) and cognitive-behavioral therapy have both been proven to be effective and are evidence based.

Topics: Adolescent; Adult; Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Behavior Therapy; Child; Citalopram; Clomipramine; Depression; Diagnosis, Differential; Eczema; Family Practice; Female; Fluoxetine; Fluvoxamine; Humans; Male; Obsessive-Compulsive Disorder; Paroxetine; Psychotherapy; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Sertraline; Surveys and Questionnaires; Time Factors; Trichotillomania

Schizophrenia is a common mental disorder that has an early onset and rates high as a cause of medical disability. Antipsychotic agents are the mainstay of treatment but response is often inadequate. Negative symptoms (disturbances in volition, social interaction and affective functions) are particularly difficult to treat and form a major obstacle to rehabilitation. A promising approach to improve response of negative symptoms has been to add a selective serotonin reuptake inhibitor (SSRI) antidepressant to antipsychotic treatment. This review examines evidence pertaining to the efficacy, tolerability, and safety of the SSRI fluvoxamine, combined with antipsychotic agents, in the treatment of negative symptoms in schizophrenia. Important methodological issues, such as differentiating primary and secondary negative symptoms, are discussed. The balance of available evidence indicates that fluvoxamine can improve primary negative symptoms in chronic schizophrenia patients treated with typical antipsychotics and suggests that it may also do so in some patients treated with clozapine. This combination is generally safe and well tolerated although, as antipsychotic drug concentrations may be elevated, attention to dose and drug monitoring should be considered appropriately. Combination with clozapine may require particular caution because of potential toxicity if serum clozapine levels rise steeply. The fluvoxamine doses effective in augmentation are lower than those usually used to treat depression. Evidence regarding the use of fluvoxamine augmentation to treat phenomena, such as obsessions and aggression, which may be associated with schizophrenia, is also examined. An important goal of future studies will be to define which patient groups can benefit from combined treatment.

Topics: Antipsychotic Agents; Drug Interactions; Drug Therapy, Combination; Fluvoxamine; Humans; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Numerous studies have demonstrated that fluvoxamine has considerable pharmacokinetic and pharmacodynamic interactions with clozapine. We conducted a 12-week, randomized, double-blind, placebo-controlled study to evaluate the effects of fluvoxamine on metabolic parameters and psychopathology in clozapine-treated patients with schizophrenia.. We recruited 85 patients who received a DSM-IV diagnosis of schizophrenia. Eligible patients were randomized to receive fluvoxamine 50mg/day plus clozapine 100mg/day or clozapine 300mg/day. We studied metabolic parameters, psychopathology, and drug levels at baseline and 4, 8, and 12weeks after the intervention. Plasma levels of clozapine, norclozapine, clozapine N-oxide, and fluvoxamine were determined using high-performance liquid chromatography with ultraviolet detection.. No significant difference was observed in baseline characteristics between the two groups. Clozapine-fluvoxamine combined treatment significantly attenuated the increments in body weight, insulin resistance, and levels of insulin, glucose, and triglycerides compared with clozapine monotherapy. Both groups exhibited significant improvements in their Positive and Negative Syndrome Scale (PANSS) total and negative scores. The combined treatment group showed significant reduction in the PANSS general psychopathology scores compared with the monotherapy group. No difference was observed in the plasma clozapine level between the two groups. The monotherapy group showed higher levels of norclozapine and clozapine N-oxide than the combined group.. Compared with clozapine monotherapy, treatment with adjunctive fluvoxamine with clozapine for 12weeks can alleviate body weight gain and metabolic abnormalities in patients with schizophrenia, without sacrificing the clinical effect. Clinicians should interpret these findings cautiously considering the short duration of this study. The study was registered at www.clinicaltrials.gov (NCT01401491).

Topics: Antipsychotic Agents; Antisocial Personality Disorder; Body Weight; Clozapine; Double-Blind Method; Drug Therapy, Combination; Female; Fluvoxamine; Follow-Up Studies; Humans; Leukocytes; Male; Metabolic Diseases; Psychiatric Status Rating Scales; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Time Factors; Treatment Outcome

The effectiveness of selective-serotonin reuptake inhibitors in the improvement of schizophrenia is a controversial issue. The aim of this study was to evaluate the effect of fluvoxamine on the symptoms of schizophrenia including positive and negative symptoms, cognitive impairment, and quality of life.. This clinical trial was performed on 68 patients with chronic schizophrenia, treated with risperidone at 22 Bahman Hospital of Qazvin, Iran during 2015 to 2016. The patients were randomly divided into control and intervention groups (34 patients per group). The control group was treated with risperidone and biperiden, whereas the intervention group received fluvoxamine, besides risperidone, and biperiden. The participants completed the Wechsler Memory Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms (SANS), and the World Health Organization Quality of Life Scale, and the findings were statistically analyzed at baseline and postintervention (8 and 10 weeks).. The mean ± SD Wechsler Memory Scale scores in the evaluated intervals (baseline, week 8, and week 10), respectively, were 70.58 ± 11.51, 70.76 ± 11.36, and 70.88 ± 11.40 in the control group and 74.76 ± 10.56, 77.76 ± 10.56, and 77.76 ± 10.73 in the intervention group (F = 126.73, P ≤ 0.001). The difference between the groups in terms of SANS and quality of life scores was significant in the specified intervals, SANS (F = 6.36, P = 0.004), and quality of life (F = 15.13, P ≤ 0.001). Nevertheless, no difference was observed in terms of Scale for the Assessment of Positive Symptoms scores (P > 0.05).. The results indicated that risperidone augmentation with fluvoxamine could significantly improve cognitive impairments and negative symptoms among patients with schizophrenia. Moreover, this augmentation led to higher quality of life among these patients.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Quality of Life; Risperidone; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Young Adult

Cognitive impairments in schizophrenia are associated with suboptimal psychosocial performance. Several lines of evidence have suggested that endoplasmic reticulum protein sigma-1 receptors were involved in cognitive impairments in patients with schizophrenia and that the sigma-1 receptor agonist fluvoxamine was effective in treating cognitive impairments in animal models of schizophrenia and in some patients with schizophrenia. A randomized, double-blind, placebo-controlled, parallel trial of fluvoxamine adjunctive therapy in patients with schizophrenia was performed. A total of 48 patients with chronic schizophrenia were enrolled. Subjects were randomly assigned to an 8-week administration of add-on fluvoxamine (n = 24, titrated up to 150 mg/d) or placebo (n =24) in a total 12-week double-blind trial. The primary outcome measure was the Cambridge Neuropsychological Test Automated Battery (CANTAB), assessing visual memory, working memory, attention, and executive function. The secondary outcome measures were the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, the Quality of Life Scale, and the Montgomery-Åsberg Depression Rating Scale. Fluvoxamine was well tolerated. No significant time × group interaction effects were observed in the scores of the CANTAB, Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, or the Montgomery-Åsberg Depression Rating Scale. However, in secondary analyses, the change from baseline to end point on the Spatial Working Memory strategy score (executive function) of CANTAB improved in the fluvoxamine group. This study suggests no major benefit of fluvoxamine adjunctive therapy to improve cognitive impairments in patients with schizophrenia. Nevertheless, a further study using a large sample size will be needed to confirm the secondary analyses findings.

Topics: Adult; Chronic Disease; Cognition Disorders; Double-Blind Method; Drug Therapy, Combination; Female; Fluvoxamine; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Quality of Life; Receptors, sigma; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor; Time Factors; Treatment Outcome

Clinical studies have shown that negative symptoms of schizophrenia unresponsive to antipsychotic given alone can improve after augmentation with SSRI antidepressant. Laboratory investigations into the mechanism of this synergism showed that co-administration of SSRI and antipsychotic produces changes in GABA(A) receptor and related systems, which differ from the effects of each drug alone. To examine the clinical relevance of these findings, the current study examined the effects of SSRI augmentation treatment on GABA(A) receptor and related systems in schizophrenia patients. Schizophrenia patients with high levels of negative symptoms unresponsive to antipsychotic treatment received add-on fluvoxamine (100 mg/d). Blood was taken before and 1, 3 and 6 wk after adding fluvoxamine and peripheral mononuclear cells (PMC) isolated. RNA encoding for GABA(A)β3, 5-HT2A, and 5-HT7 receptors, PKCβ2, and brain-derived neurotrophic factor (BDNF) was assayed with real-time RT-PCR. Plasma BDNF protein was assayed using ELISA. Clinical symptoms were assessed with validated rating scales. We found significant increase in mRNA encoding for GABA(A)β3 and 5-HT2A, 5-HT7 receptors and BDNF and a reduction in PKCβ2 mRNA. Plasma BDNF protein concentrations were increased. There were significant correlations among the genes. Clinical symptoms improved significantly. mRNA expression of PKCβ2, 5-HT2A and 5-HT7 showed significant associations with clinical symptoms. Combined SSRI+antipsychotic treatment is associated with changes in GABA(A) receptor and in related signalling systems in patients. These changes may be part of the mechanism of clinically effective drug action and may prove to be biomarkers of pharmacological response.

Topics: Antidepressive Agents; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Biomarkers, Pharmacological; Brain-Derived Neurotrophic Factor; Drug Synergism; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Leukocytes, Mononuclear; Male; Protein Kinase C; Protein Kinase C beta; Psychiatric Status Rating Scales; Receptor, Serotonin, 5-HT2A; Receptors, GABA-A; RNA, Messenger; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Augmentation with low-dose fluvoxamine (50-100 mg/day) to antipsychotic treatment may improve the negative symptoms in schizophrenic patients, but involves a risk of drug-drug interaction. We studied the effects of fluvoxamine on plasma concentrations of haloperidol and reduced haloperidol, and their clinical symptoms, in haloperidol treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving haloperidol 6 mg/day were additionally treated with incremental doses of fluvoxamine for 6 weeks (25, 75 and 150 mg/day for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the three fluvoxamine doses. Geometric mean of haloperidol concentrations during coadministration of fluvoxamine 25, 75 and 150 mg/day were 120% (95%CI; 114-127%), 139% (95%CI; 130-149%), and 160% (95%CI; 142-178%) of those before fluvoxamine coadministration, respectively. We found positive correlations between increase in plasma haloperidol concentrations and plasma fluvoxamine concentrations. Scores in negative symptoms were significantly reduced after fluvoxamine coadministration, whereas no changes were observed in the other psychiatric symptoms or any subgrouped side effects. Therefore, this study indicates that fluvoxamine increases plasma haloperidol concentrations in a dose-dependent manner. However, relatively small elevations in haloperidol concentration did not lead to the development of extrapyramidal symptoms under the conditions of this study.

Topics: Adult; Antipsychotic Agents; Dose-Response Relationship, Drug; Drug Synergism; Female; Fluvoxamine; Haloperidol; Humans; Inpatients; Male; Middle Aged; Schizophrenia; Selective Serotonin Reuptake Inhibitors

The objective of the present study was to compare the efficacy and adverse effects of olanzapine plus fluvoxamine and those of olanzapine alone, in schizophrenic patients with acute exacerbation. A randomized, placebo-controlled, 6-week trial was carried out at a University Hospital in Bangkok, Thailand. The efficacy and adverse effects were assessed biweekly by using the Brief Psychiatric Rating Scale (BPRS) and the Udvalg for Kliniske Undersogelser side-effect scale, respectively. Twenty schizophrenic patients with acute exacerbation were randomly assigned to receive olanzapine plus fluvoxamine or olanzapine alone. The study found that the means of BPRS total and BPRS general psychopathology score changes were significantly larger in olanzapine plus fluvoxamine group (P = 0.037 and P = 0.045, respectively). The incidence of treatment adverse effects is comparable. In conclusion, the study findings suggest that fluvoxamine augmentation to olanzapine is well tolerated and more effective than olanzapine alone for short-term (6-week) treatment of an acute exacerbation of schizophrenia. Due to a number of limitations, further studies are warranted to confirm.

Topics: Acute Disease; Adult; Antipsychotic Agents; Benzodiazepines; Drug Therapy, Combination; Female; Fluvoxamine; Hospitals, Psychiatric; Humans; Male; Middle Aged; Olanzapine; Prospective Studies; Schizophrenia; Schizophrenic Psychology; Selective Serotonin Reuptake Inhibitors; Thailand; Treatment Outcome

Olanzapine, an atypical antipsychotic agent, is a substrate of the cytochrome P4501A2 (CYP1A2) enzyme. Administration of a potent CYP1A2 inhibitor (eg, fluvoxamine) may alter the pharmacokinetics of olanzapine. This study investigated the pharmacokinetic interactions between olanzapine and fluvoxamine in patients with schizophrenia. Ten male smokers were administrated a single dose of olanzapine 10 mg at baseline, followed by 2 weeks of fluvoxamine 50 mg/day and another 2 weeks of fluvoxamine 100 mg/day. Olanzapine 10 mg was given at day 10 during each fluvoxamine treatment. After pretreatment with fluvoxamine, the area under the curve, maximal plasma concentration, and half-time of olanzapine were significantly increased by 30% to 55%, 12% to 64%, and 25% to 32%, respectively. Volume of distribution and apparent clearance were significantly reduced by 4% to 26% and 26% t O 38%, respectively, after administration of fluvoxamine. Increases in area under the plasma concentration-time curve from time 0 to infinity appear to be dose dependent. Presumably, altered olanzapine pharmacokinetics are attributed to the inhibition of CYP1A2. Patients treated with the combination of olanzapine and fluvoxamine should be monitored carefully.

Topics: Adult; Area Under Curve; Benzodiazepines; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Antagonism; Drug Therapy, Combination; Fluvoxamine; Half-Life; Humans; Olanzapine; Schizophrenia; Smoking; Taiwan

Olanzapine is a substrate of the cytochrome P450 enzyme (CYP) 1A2. In this study, pharmacokinetic interactions and clinical effects of adding the CYP1A2 inhibitor fluvoxamine to steady-state olanzapine was examined in patients suffering from schizophrenia. Eight patients had been treated for at least 3 months with 10 to 20 mg/day olanzapine. Fluvoxamine (100 mg/day) was added (week 0) to the olanzapine treatment and continued for 8 weeks. Concentrations of olanzapine and its metabolite N-desmethylolanzapine and of fluvoxamine were analyzed at weeks 0, 1, 4, and 8. Addition of fluvoxamine resulted in a 12% to 112% ( < 0.01) increase of olanzapine from 31 +/- SD 15 ng/mL (week 0) to 56 +/- 31 ng/mL (week 8) in all patients. N-desmethylolanzapine concentrations were not significantly changed ( > 0.05). Fluvoxamine concentrations were 48 +/- 26 ng/mL on week 1 and 83 +/- 47 ng/mL on week 8. It is concluded that fluvoxamine affects olanzapine degradation and thus increases olanzapine concentrations. Although the combination was well tolerated in this sample and the negative symptom response appeared to be favorable in at least five patients, the combination therapy of olanzapine and fluvoxamine should be used cautiously and should be controlled by therapeutic drug monitoring to avoid olanzapine-induced side effects or intoxications.

Topics: Adult; Benzodiazepines; Chemotherapy, Adjuvant; Chronic Disease; Drug Interactions; Female; Fluvoxamine; Follow-Up Studies; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Prospective Studies; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Time Factors

We investigated the efficacy and safety of augmenting risperidone with fluvoxamine for the treatment of residual positive and negative symptoms in patients with chronic schizophrenia who had shown an incomplete response to risperidone. A total of 30 patients completed the open trial over a 12-week period during which fluvoxamine was added to risperidone. The result from the positive and negative syndrome scale (PANSS) and Simpson-Angus extrapyramidal effects (S-A) scale were examined at baseline, 1, 2, 4, 8 and 12 weeks of treatment. There were no significant differences in PANSS positive, negative and general psychopathology scores, or in S-A scale scores at any point during the treatment. These results suggest that fluvoxamine appears to be ineffective in augmenting the risperidone treatment response in chronic schizophrenic patients. Further controlled trials will be needed to confirm this observation.

Topics: Antipsychotic Agents; Chronic Disease; Drug Interactions; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Fluvoxamine; Humans; Male; Schizophrenia

Clozapine treatment is associated with side-effects such as blood cell dyscrasias and weight gain. Increased plasma levels of the cytokines and soluble cytokine receptors leptin, tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, as well as toxic metabolites of clozapine, have been suggested as the basis for these side-effects,. This study examined whether the coadministration of the selective serotonine reuptake inhibitor fluvoxamine, which interferes with clozapine's hepatic metabolism, affects the immunomodulation by clozapine and some of its side-effects.. The following parameters were measured: circulating levels of the cytokines and soluble receptors, plasma concentrations of clozapine and its metabolite N-desmethylclozapine, body weight and blood cell counts in 11 and 12 schizophrenic inpatients on combined and monotherapy, respectively, before and during the first 6 weeks of medication.. On the basis of comparable plasma levels of clozapine and N-desmethylclozapine, the coadministration of fluvoxamine 1) attenuated and delayed the clozapine-induced increase in TNF-alpha plasma levels, 2) enhanced and accelerated the clozapine-induced increase in leptin plasma levels without significant effect on clozapine-induced weight gain, and 3) decreased granulocyte counts.. As clozapine, its metabolite N-desmethylclozapine and fluvoxamine are unlikely to make these differences, other metabolites might be responsible. The coadministration of clozapine and fluvoxamine offers the opportunity to investigate further the putative associations between certain metabolites, immunomodulation and these side-effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Cell Count; Body Weight; Clozapine; Cytokines; Drug Interactions; Drug Therapy, Combination; Female; Fluvoxamine; Granulocytes; Humans; Leptin; Male; Middle Aged; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Obsessive-compulsive-related disorders are frequently comorbid with schizophrenia. The existence of obsessive and compulsive symptoms in patients with schizophrenia represents one of the most severe types of psychotic disorders and may predict a poor prognosis in most cases. Previous pilot studies and case reports have shown that the condition of some patients with schizophrenia did not exacerbate and even improved when serotonin reuptake inhibitors (SSRIs) were added to their standard neuroleptic regimen. The aim of this study was to evaluate the efficacy of a combination treatment of an SSRI (fluvoxamine) and standard neuroleptics for the treatment of obsessive-compulsive (OC) symptomatology in patients with schizophrenia compared with administration of neuroleptics only. Thirty inpatients who met DSM-IV criteria for schizophrenia and also had prominent OC symptoms were randomly divided into two groups. Fourteen patients were treated with conventional neuroleptics and fluvoxamine in doses of 100 to 200 mg/day for 8 weeks. Sixteen patients comprised a control group and received only their previous therapeutic neuroleptic therapy. The patients were assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression Scale (CGI) at baseline and endpoint. Side effects were assessed weekly. The data were analyzed using an analysis of variance. A considerable reduction in PANSS (34.3%) and Y-BOCS (29.4%) scores was noted, and CGI scores decreased moderately in both groups. None of the patients showed an acute exacerbation at the end of the study. Side effects were mild and easily tolerated in most patients. This open, randomized, controlled study reveals that coadministration of fluvoxamine, an SSRI, and neuroleptics in patients with schizophrenia and OC symptoms was associated with specific improvements of these symptoms. Thus, the use of an SSRI in treating a patient with schizophrenia and OC symptomatology may be warranted and safe. Other implications of the findings, including general safety of the combined pharmacotherapy and the use of new antipsychotic medications, are also discussed.

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Compulsive Behavior; Female; Fluvoxamine; Haloperidol; Humans; Male; Middle Aged; Obsessive Behavior; Perphenazine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

The efficacy and safety of adding fluvoxamine to antipsychotic treatment in schizophrenic patients with mixed positive and negative symptoms was examined. Fifty-three patients selected for persistent negative and positive symptoms who were receiving antipsychotic treatment were randomly allocated to additional fluvoxamine (50-100 mg/day) or placebo in a double-blind manner. Fluvoxamine was associated with significant improvement in negative symptoms (Scale for the Assessment of Negative Symptoms) compared to placebo. The combination was well tolerated. Fluvoxamine augmentation of antipsychotics is safe in chronic schizophrenic patients with mixed positive and negative symptoms and may ameliorate negative symptoms in such patients.

Topics: Adult; Anti-Anxiety Agents; Antipsychotic Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Middle Aged; Schizophrenia; Severity of Illness Index; Treatment Outcome

Obsessive-Compulsive (OC) symptoms are observed in a substantial proportion of schizophrenic patients and pose a significant therapeutic challenge. Based on findings of the benefit of the anti-obsessive agent clomipramine, we designed an open-label study to examine the effect of adding the serotonin-selective reuptake inhibitor (SSRI) fluvoxamine to the ongoing antipsychotic regimen of schizo-obsessive patients. The study population consisted of ten neuroleptic-stabilized chronic schizophrenic patients with OC symptoms. Fluvoxamine (up to 150 mg/day) was added to the ongoing antipsychotic treatment, which remained unchanged for the entire 12-week trial period. The patients were evaluated before the trial and at weeks 1, 2, 4, 6, 8 and 12 (end point) with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Schedule for Assessment of Positive Symptoms and the Schedule for Assessment of Negative Symptoms. The results showed a significant improvement in obsessions (P < 0.02) (but not compulsions) and both positive (P < 0.01) and negative (P < 0.05) schizophrenic symptoms. By the end of the trial, three patients showed a more than 50% reduction in the Y-BOCS score, with complete amelioration of the OC symptoms in one of them. Three patients were dropped from the study during the first 4 weeks, two because of aggressiveness and one because of psychotic exacerbation. No exacerbation or new onset of extrapyramidal side-effects (EPS), as measured by the Barnes Akathisia Scale (BARS) and the Simpson-Angus Scale (SAS), was noted during the course of the trial and there were no other significant clinical side-effects of fluvoxamine addition. We conclude that fluvoxamine may be an effective adjunctive agent in some schizo-obsessive patients.

Topics: Adult; Female; Fluvoxamine; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Fluvoxamine (FLUVOX) is an inhibitor of the cytochrome P450 isoenzyme 1 A2 and thereby inhibits clozapine (CLOZ) metabolism. We performed an open clinical study to gather experience in necessary dosages, plasma levels, side effects and clinical efficiency of the coadministration of the two drugs. Eighteen psychotic patients were studied. 50 mg FLUVOX were given throughout the study period, while the CLOZ dosage was increased individually (week 5: 96.9+/-37.2 mg). After 5 weeks the plasma concentrations were as follows: CLOZ 252+/-174 ng/ml, N-desmethylclozapine (DM-CLOZ) 143+/-74 ng/ml and clozapine N-oxide (CLOZ N-OX) 30+/-14 ng/ml. There were no differences in side effects, especially sedation, after 5 weeks compared to the pretreatment condition. Moreover, we found a significant improvement in measures of cognitive speed which might be regarded as a measure of vigilance. The BPRS scores dropped continuously until week 5 (pretreatment: 53.3+/-13.4; week 5: 33.2+/-12.9) and 5 patients were considered treatment responders (BPRS reduction > 50%). Ten patients continued the combination treatment after the study period and 9 of these patients were in clinical remission when discharged. Given strict therapeutic drug monitoring, coadministration of FLUVOX and CLOZ seems to be a safe and efficient treatment strategy with a low occurrence of the side effects associated with CLOZ treatment. This might be due to additive effects of the two drugs and/or metabolic interaction.

Topics: Adult; Anti-Anxiety Agents; Antipsychotic Agents; Clozapine; Depressive Disorder; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Psychotic Disorders; Schizophrenia; Schizophrenia, Paranoid

Combining fluvoxamine and clozapine may be a strategy to improve therapeutic effects on negative symptoms in schizophrenic patients. Fluvoxamine, however, markedly inhibits the metabolism of clozapine, and hazardous side effects may result. This study prospectively investigated the safety and tolerability of an add-on therapy with fluvoxamine to a clozapine monotherapy in schizophrenic patients. Sixteen schizophrenic patients received 50 mg fluvoxamine as a comedication after having reached steady-state conditions under clozapine monotherapy. Patients were monitored for subjective adverse events, laboratory parameters, EEG and ECG recordings, orthostatic hypotension and their psychopathology. Concomitantly, serum concentrations of clozapine and metabolites were measured during monotherapy and after addition of fluvoxamine. In all patients, the serum concentrations of clozapine and metabolites were markedly increased (average: 2-3 fold, up to 5 fold for clozapine) after addition of fluvoxamine. Side effects remained almost unchanged in frequency and severity in spite of the pharmacokinetic interactions. ECG or laboratory parameters and orthostatic tests were similar under monotherapy and comedication. Minimal increases of EEG abnormalities were observed, but they were not associated with clinical impairment. Epileptic activities were always absent. The psychopathology improved which continued after start of the comedication. Though the addition of fluvoxamine to clozapine medication was well tolerated and critical side effects were absent, the combined treatment should be controlled by drug monitoring, as serum concentrations of clozapine increased to unpredictably high levels. Further studies have to find out if the combined treatment could be advantageous to clozapine monotherapy.

Topics: Adolescent; Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Matched-Pair Analysis; Middle Aged; Prospective Studies; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

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.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Drug Interactions; Female; Fluvoxamine; Humans; Male; Middle Aged; Paroxetine; Prospective Studies; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Smoking

There is considerable evidence that adding selective serotonin reuptake inhibitor (SSRI) antidepressants to antipsychotic treatment improves negative symptoms of schizophrenia. This augmentation effect may be due to "nonspecific" antidepressant action or be specifically related to action on the serotonergic system. This study examined the serotonergic specificity of SSRI augmentation by comparing an SSRI antidepressant with a comparably effective antidepressant acting via the noradrenergic system. Consenting patients having chronic schizophrenia with prominent negative symptoms were studied. Either fluvoxamine or maprotiline was added to their regular antipsychotic treatment in a double-blind manner for 6 weeks. Patients were assessed using the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Neurological Rating Scale for Extrapyramidal Side Effects. Twenty-five patients completed the study. Negative symptoms improved significantly in the fluvoxamine group, but not in the maprotiline group. MADRS scores, which were low, did not change significantly in either group. Positive symptoms were not affected by either treatment. It is concluded that the mechanism by which fluvoxamine augmentation improves negative symptoms involves the serotonergic system and is distinct from its antidepressant action.

Topics: Adult; Antidepressive Agents; Double-Blind Method; Female; Fluvoxamine; Humans; Male; Maprotiline; Middle Aged; Psychiatric Status Rating Scales; Receptors, Serotonin; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Four patients with chronic schizophrenia were treated with a combination of fluvoxamine, haloperidol, and benztropine. The combination significantly impaired performance on tests of delayed recall memory and attentional function. Haloperidol concentrations in serum were monitored in three patients and were robustly elevated by fluvoxamine.

Topics: Adult; Benztropine; Chronic Disease; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Fluvoxamine; Haloperidol; Humans; Male; Middle Aged; Neurologic Examination; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Adolescent; Adult; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Fluvoxamine; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Child; Clozapine; Drug Therapy, Combination; Fluvoxamine; Humans; Male; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Clozapine (CLZ) is metabolized via cytochrome P450 CYP1A2 to N-desmethylclozapine (NCLZ). Smoking induces CYP1A2 thereby increasing clozapine metabolism whereas fluvoxamine inhibits CYP1A2. Studies suggest that the beneficial effect of fluvoxamine augmentation in raising serum clozapine concentrations also occurs when serum concentrations are low due to smoking. Yet, little is known about the influence of fluvoxamine augmentation on clozapine serum concentrations in smoking versus non-smoking patients.. The CLZ monotherapy smoking group showed lower values of C/D CLZ of -38.6% (p < 0.001), C/D NCLZ -35.6% (p < 0.001) and a higher MPR (p = 0.021) than in the non-smoking group. The combination of CLZ and fluvoxamine in non-smoking patients led to higher C/D values: C/D CLZ +117.9% (p < 0.001), C/D NCLZ +60.8% (p = 0.029) while the MPR did not differ between groups (p = 0.089). Changes were comparable to fluvoxamine augmentation in the smoking group with increased C/D CLZ of +120.1% (p < 0.001), C/D NCLZ of +85.8% (p < 0.001) and lower MPR (p = 0.006).. Smoking in clozapine monotherapy reduced median dose-adjusted serum concentrations more than a third. Combined treatment with fluvoxamine and clozapine led to higher median C/D values in both, smokers and non-smokers. The opposing effects of CYP1A2 induction by smoking and inhibition by fluvoxamine on clozapine serum concentrations balanced out.

Topics: Adult; Aged; Antipsychotic Agents; Cigarette Smoking; Clozapine; Comorbidity; Cytochrome P-450 CYP1A2 Inhibitors; Drug Synergism; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Middle Aged; Schizophrenia; Young Adult

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Outcome Assessment, Health Care; Schizophrenia

Previous studies into the mechanism of SSRI-antipsychotic synergism in our laboratory identified unique changes in the brain, particularly in the γ-aminobutyric acid (GABA)-A receptor and its modulators. This study examined the role of brain derived neurotrophic factor (BDNF)-cAMP response element binding (CREB) protein signaling pathways, including protein kinase B (AKT), glycogen synthase kinase (GSK)-3β and related molecules in the molecular response to haloperidol, fluvoxamine, combined haloperidol+fluvoxamine and clozapine treatments in rat frontal cortex, hippocampus and primary cortical neuronal cultures. The effect of fluvoxamine augmentation on BDNF-CREB pathways in peripheral mononuclear cells (PMC׳s) of medicated schizophrenia patients was also studied. Chronic haloperidol (1mg/kg) +fluvoxamine (10mg/kg) treatment increased TrkB receptor and BDNF expression levels, and the phosphorylation of AKT/CREB/GSK-3β, compared to the individual drugs in rat brain. In addition, haloperidol+fluvoxamine treatment improved cognitive functions in rats, indicating that the molecular changes may have a role in behavioral improvement. In primary neuronal cell cultures, pretreatment with a selective PI3K inhibitor abolished the haloperidol+fluvoxamine-induced phosphorylation of AKT and GSK-3β, but did not affect the upregulation of CREB phosphorylation. In the clinic, PMC׳s of treated patients showed upregulation of mRNA expression and protein levels of BDNF, CREB and AKT after addition of fluvoxamine. Analyses of PMC genes and proteins showed significant inter-correlations and some gene changes correlated with improvement in negative and cognitive symptoms. Our study provides new knowledge of the molecular mechanisms of symptom amelioration in schizophrenia and may advance development of new drugs for this disease and other neuropsychiatric disorders.

Topics: Adult; Animals; Antipsychotic Agents; Brain-Derived Neurotrophic Factor; CREB-Binding Protein; Drug Combinations; Embryo, Mammalian; Female; Fluvoxamine; Haloperidol; Hippocampus; Humans; In Vitro Techniques; Male; Middle Aged; Rats; Rats, Sprague-Dawley; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Signal Transduction

Topics: Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 Enzyme Inhibitors; Drug Therapy, Combination; Fluvoxamine; Humans; Male; Mutism; Schizophrenia; Young Adult

Cognitive deficits are a core symptom of schizophrenia. It is controversial whether antidepressants could improve cognitive symptoms in schizophrenia patients. The present study was designed to identify the therapeutic effect of antidepressants on cognitive deficits in schizophrenia. In the present study, adolescent rats were repeatedly exposed to dizocilpine, which can induce cognitive deficits associated with schizophrenia. Then these rats were treated by six antidepressants (fluvoxamine, sertraline, paroxetine, escitalopram, venlafaxine, mirtazapine) or vehicle. The rats in the control group were exposed to vehicle during the study. Lastly, all rats' spatial memory (a major part of cognition) was assessed using the Morris water maze (MWM) test, and the density of hippocampal parvalbumin (PV) interneurons was evaluated to explore possible mechanisms underlying spatial memory change in schizophrenia. The results of the present study supported the hypothesis of a therapeutic effect of fluvoxamine and escitalopram on spatial memory deficit induced by dizocilpine. Additionally, the data of the present study suggested that fluvoxamine and escitalopram remitted hippocampal PV interneuron reduction induced by dizocilpine. The neuroprotective effect of fluvoxamine and escitalopram may partly explain the therapeutic effect of antidepressants on spatial memory deficit in schizophrenia patients.

Topics: Animals; Antidepressive Agents; Cell Count; Citalopram; Cognition; Cognitive Dysfunction; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluvoxamine; Hippocampus; Interneurons; Male; Maze Learning; Memory Disorders; Mianserin; Mirtazapine; Paroxetine; Rats; Rats, Sprague-Dawley; Schizophrenia; Schizophrenic Psychology; Sertraline; Spatial Memory; Venlafaxine Hydrochloride

Verbal memory impairment in schizophrenia is associated with abnormalities in gamma-aminobutyric acid (GABA)-ergic and brain-derived neurotrophic factor (BDNF) systems. Recent evidence from animal and clinical studies that adding fluvoxamine to antipsychotics alters the expression of transcripts encoding for the GABA-A receptor and BDNF led us to postulate that fluvoxamine augmentation may improve memory in schizophrenia. To test this, we examined the effect of add-on fluvoxamine on verbal memory and other cognitive functions and related it to the expression of mRNA coding for the GABA-A receptor and BDNF in peripheral mononuclear cells (PMC) of schizophrenic patients. Twenty-nine patients completed a 6-week study in which fluvoxamine (100 mg/day) was added to ongoing antipsychotic treatment. Verbal memory, abstraction working memory, object and face recognition, and psychomotor speed and clinical symptoms were assessed at baseline and after 3 and 6 weeks of treatment. Blood samples were taken at baseline and weeks 1, 3, and 6 and PMC was assayed for the GABA-A beta3 receptor and BDNF mRNA by quantitative real-time reverse transcription-PCR. Associative and logical verbal memory improved significantly and showed a significant correlation with changes in PMC BDNF and GABA-A beta3 receptor mRNA, which increased during treatment. Abstraction and object recognition improved, but this did not correlate with PMC measures. Negative and positive symptoms improved significantly; the latter showed significant correlations with changes in PMC measures. Addition of fluvoxamine to antipsychotics improves verbal memory. It is postulated that the mechanism involves enhanced GABA-A receptor/BDNF-dependent synaptic plasticity in the hippocampus.

Topics: Adult; Antipsychotic Agents; Brain-Derived Neurotrophic Factor; Drug Therapy, Combination; Female; Fluvoxamine; Gene Expression Regulation; Humans; Leukocytes, Mononuclear; Male; Memory; Receptors, GABA-A; RNA, Messenger; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Verbal Learning; Young Adult

Among antiserotonergic second generation antipsychotics (SGA), particularly treatment with clozapine (CLZ) is associated with the development of second-onset obsessive compulsive symptoms (OCS) in schizophrenia. However, less is known regarding the factors that increase the individual susceptibility for the development of SGA-associated second-onset OCS in schizophrenia. Here we present the case of a 29-year-old female patient with disorganized schizophrenia who exhibited OCS due to fluvoxamine-induced elevation of CLZ serum levels via inhibition of CYP 1A2 und 2C19. The severity of the observed OCS featured an association with CLZ serum levels. The case illustrates the interaction between fluvoxamine add-on and CLZ serum levels on the development of OCS in schizophrenia and emphasizes the need of regular therapeutic drug monitoring.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Fluvoxamine; Humans; Obsessive-Compulsive Disorder; Schizophrenia

Topics: Clozapine; Fluvoxamine; Humans; Schizophrenia

Although clozapine is the only antipsychotic agent to have demonstrated superior efficacy in treatment-refractory schizophrenia, one- to two-thirds of patients do not respond adequately despite acceptable dosages and plasma levels. Moreover, a significant number of patients stop the therapy for various reasons, including its side effects, many of which are thought to be related to its active metabolite, norclozapine. However, combining clozapine with the SSRI antidepressant fluvoxamine decreases norclozapine formation by inhibiting the CYP450 1A2 isoenzyme. Lowering norclozapine levels in this way while maintaining therapeutic clozapine levels increases the clozapine: norclozapine ratio; the potential benefits include both a reduction of such side effects as sedation, weight gain, metabolic disturbances, and neutropenia, and an increase in efficacy. The optimal ratio of clozapine to norclozapine has not yet been defined, but a ratio of two or more implies that saturation of clozapine metabolism has been reached. We hypothesize that co-administration of clozapine and fluvoxamine at dosages that will produce therapeutic plasma levels of clozapine and a clozapine: norclozapine ratio of two or more will increase efficacy and tolerability of clozapine therapy in treatment-resistant schizophrenic patients.

Topics: Clozapine; Cytochrome P-450 CYP1A2 Inhibitors; Drug Combinations; Fluvoxamine; Humans; Schizophrenia

The abuse of methamphetamine causes abnormal behaviors which are indistinguishable from schizophrenia in humans. Recent reports have shown that selective serotonin reuptake inhibitors (SSRIs) have beneficial effects on methamphetamine-related behaviors, including behavioral sensitization and rewarding effects in animals. However, the exact mechanisms by which SSRIs affect methamphetamine-related behaviors are not yet clear. The present study was designed to investigate the effects of SSRIs on the development of methamphetamine-induced behavioral sensitization and rewarding effects in mice. Behavioral sensitization was measured by examining the locomotor activity of mice in a tilting cage after repeated injections of methamphetamine. Repeated administration of methamphetamine significantly induced a behavioral sensitization. Some SSRIs (fluoxetine and fluvoxamine), which have sigma-1 receptor agonistic activity, inhibited the development of methamphetamine-induced behavioral sensitization. Fluoxetine also dose-dependently attenuated the rewarding effects of methamphetamine as measured by the conditioned place preference paradigm. Furthermore, the sigma-1 receptor antagonist NE-100 significantly reversed the inhibitory effects of fluoxetine on methamphetamine-induced behavioral sensitization and rewarding effects. These results suggest that sigma-1 receptor agonistic activity might be involved in the attenuating effects of fluoxetine and fluvoxamine on methamphetamine-induced behavioral sensitization and rewarding effects.

Topics: Animals; Anisoles; Behavior, Animal; Disease Models, Animal; Fluvoxamine; Methamphetamine; Mice; Propylamines; Rats; Receptors, sigma; Reward; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor

Topics: Anti-Anxiety Agents; Cognition Disorders; Epilepsy; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Female; Fluvoxamine; Humans; Long QT Syndrome; Middle Aged; Multiple Sclerosis; Obsessive-Compulsive Disorder; Potassium Channel Blockers; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Aryl Hydrocarbon Hydroxylases; Clomipramine; Clozapine; Comorbidity; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Fluoxetine; Fluvoxamine; Humans; Male; Obsessive-Compulsive Disorder; Schizophrenia; Selective Serotonin Reuptake Inhibitors

There is evidence that combining selective serotonin reuptake inhibitor (SSRI) antidepressant and antipsychotic drugs may improve negative symptoms in schizophrenia and resistant symptoms in obsessive-compulsive and affective disorders. To examine the mechanism of action of this treatment we investigated the molecular modulation of γ-aminobutyric acid-A (GABA(A)) receptor components and biochemical pathways associated with GABA(A) receptor function following administration of the SSRI fluvoxamine (Flu) combined with the first-generation antipsychotic haloperidol (Hal) and compared it to the individual drugs and the atypical antipsychotic clozapine (Clz). We analysed prefrontal cortices of Sprague-Dawley rats injected intraperitoneally (i.p.) with the combination of Flu (10 mg/kg) and Hal (1 mg/kg), each drug alone, or Clz (10 mg/kg) after 30 min and 1 h. We found that haloperidol plus fluvoxamine (Hal-Flu) co-administration, and Clz, decreased the level of GABAAβ2/3 receptor subunit in the cytosolic fraction, and increased it in the membrane compartment in rat PFC. Flu or Hal alone did not produce changes in GABAAβ2/3 receptor protein expression. Additionally, Hal-Flu and Clz regulated molecular signalling pathways that modulate GABA(A) receptor function, including protein kinase C (PKC) and extracellular signal-regulated kinase-2 (ERK2). In primary cortical culture, short-term treatment (15 min) with Hal-Flu combination and Clz increased GABAAβ subunit phosphorylation levels. Pretreatment of the cells with PKC inhibitor abolished the effect of the combined treatment, or Clz on phosphorylation of GABA(A) receptor. Inhibition of ERK2 did not alter the effect of drugs on GABA(A) receptor phosphorylation levels. Our findings provide evidence that the combined treatment regulates GABA(A) receptor function and does so via a PKC-dependent pathway.

Topics: Animals; Antidepressive Agents; Antipsychotic Agents; Cells, Cultured; Clozapine; Dopamine; Drug Therapy, Combination; Fluvoxamine; Haloperidol; Male; Mitogen-Activated Protein Kinase 1; Mood Disorders; Obsessive-Compulsive Disorder; Phosphorylation; Prefrontal Cortex; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Topics: Caffeine; Depression; Drug Interactions; Fluvoxamine; Humans; Risperidone; Schizophrenia; Smoking

Topics: Cognition Disorders; Female; Fluvoxamine; Humans; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Young Adult

Topics: Antipsychotic Agents; Clozapine; Comorbidity; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Fluvoxamine; Humans; Obsessive-Compulsive Disorder; Risk Factors; Schizophrenia; Schizophrenic Psychology; Selective Serotonin Reuptake Inhibitors

To study the impact of risperidone (RISP) on clozapine (CLZ) biotransformation in vitro in microsomal fractions containing varying expression of CYP oxidases and in vivo in patients.. Human liver microsomes (n= 11) were assessed for expression of CYPs 1A2, 2D6 and 3A4, because these enzymes mediate RISP and CLZ oxidation. Inhibition of CLZ oxidation by RISP was assessed. Plasma CLZ elimination was estimated in patients with schizophrenia who received either CLZ alone or the CLZ-RISP combination (n= 10 per group).. (i) The CYP3A4 and CYP1A2 inhibitors ketoconazole and fluvoxamine inhibited CLZ oxidation to varying extents in individual microsomal fractions. (ii) RISP did not inhibit CLZ oxidation, regardless of variations in CYP expression. (iii) RISP co-administration did not impair CLZ clearance.. No evidence was found for CYP-mediated inhibitory or pharmacokinetic interactions between RISP and CLZ. Occasional literature reports of such interactions may involve other pathways that participate in CLZ disposition.

Topics: Adult; Antipsychotic Agents; Biotransformation; Chromatography, High Pressure Liquid; Clozapine; Cytochrome P-450 Enzyme System; Drug Combinations; Drug Interactions; Female; Fluvoxamine; Humans; Ketoconazole; Male; Microsomes, Liver; Middle Aged; Risperidone; Schizophrenia; Young Adult

Antipsychotic treatment combined with Selective Serotonin Reuptake Inhibitor (SSRI) antidepressant can improve negative symptoms in schizophrenic patients that are unresponsive to antipsychotic drugs alone. The mechanism of this therapeutic effect is not clear. The current study examined molecular changes induced by the combined treatment in human peripheral mononuclear cells (PMC) in order to get insight into its mechanism of action. Gene expression profile of PMC from antipsychotic-treated patients was examined before addition of the SSRI fluvoxamine, and 3 and 6 weeks after. Gene expression patterns screened with a cDNA array, comprising 1176 genes, revealed homologous changes in a range of transcripts related to G-protein coupled receptors (GPCR). Genes related to GPCR-family were assayed using customized cDNA array and the results verified by real-time RT-PCR. The mRNA expression of chemokine receptors, IL8RA and CCR1, and of RGS7 was significantly down-regulated following fluvoxamine augmentation. The clinical assessments showed improvement in negative symptoms following the combined treatment. The transcriptional analysis suggests that the therapeutic mechanism of the combined antipsychotic-fluvoxamine treatment may involve genes associated with G-protein coupled receptors (GPCR). Our findings suggest that gene expression changes in PMC may be useful in investigating the mechanism of drug action in schizophrenia.

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; DNA Primers; DNA, Complementary; Drug Therapy, Combination; Female; Fluvoxamine; Gene Expression; Humans; Male; Monocytes; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA; Schizophrenia

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Fluvoxamine; Humans; Male; Meige Syndrome; Olanzapine; Risperidone; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Although clozapine currently remains the most effective option in treatment-resistant schizophrenia, approximately 40-70% of antipsychotic-resistant patients do not respond, or respond only partially, to clozapine. Because clozapine-resistant patients have limited alternative treatment options, in this study we propose a clozapine augmentation strategy with evidence-based support for some of them.. Clozapine-resistance is often of metabolic origin. Clozapine is metabolized by N-oxidation and N-demethylation in the liver, predominantly by CYP450 1A2. Due to the influence of inhibitors, inducers, and genetic factors on CYP450 1A2-activity, there is extensive interindividual variability in clozapine plasma concentrations at a fixed dose. Consequently, monitoring of clozapine plasma concentrations is recommended. Several studies have suggested a significantly higher response rate at clozapine plasma concentration of less than 350 microg/l. Unfortunatly, some patients, especially young male smokers, do not achieve this minimum plasma concentration, even at doses higher than 900 mg/day and are nonresponders.. We report the case of a 30 year-old smoker suffering from refractory schizophrenia, and responding poorly to treatments, including clozapine. Monitoring of the clozapine plasma concentration showed a very low level of clozapine, below the minimal effective dose of 350 microg/l. We initially suspected noncompliance with the treatment regime, but genetic analyses revealed another explanation: a gene polymorphism of the CYP450 1A2, principal enzyme that breaks down clozapine. The variability of CYP450 1A2 is explained by a gene polymorphism in intron 1. The A/A genotype confers high CYP450 1A2 inductivity in smokers. Certain smoking patients with A/A polymorphism have ultrarapid CYP450 1A2 activity, which causes the patient to metabolize clozapine too quickly. These patients do not respond to clozapine, even with doses higher than 900 mg/day. However, several factors can counter this elevated CYT activity, in particular fluvoxamine. The interaction between clozapine and fluvoxamine occurs via the inhibition of CYP450 1A2. Several studies have shown that administration of fluvoxamine to patients receiving clozapine therapy may increase the steady-state serum concentrations of clozapine by a factor of 5. Low doses of fluvoxamine inhibit the CYT activity, enough to raise the level of clozapine even when the dose of clozapine was reduced by 50%. The patient unfortunately developed a maniac episode during treatment with fluvoxamine, despite the absence of a previous history of bipolar illness, and we had to initiate treatment with lithium. Together, the three medications stabilized his condition satisfactorily for eight months. We describe three additional cases of treatment-refractory patients with schizophrenia and low-clozapine plasma levels despite high doses. They exhibited similar metabolic abnormality, as confirmed by a caffeine test, because plasma caffeine ratios reflect CYP450 1A2 activity. We then describe its correction, with low doses of fluvoxamine. These patients became responders when the plasma levels increased above the threshold.. Consequently, we propose a therapeutic drug monitoring strategy. In the case of a clozapine-resistant schizophrenic patient, plasma clozapine levels should be tested. If the rate is normal, the resistance is not metabolic in origin. If the rate is low, a caffeine test should be done. If the results are normal, the patient is noncompliant with the treatment. If the caffeine test is abnormal, metabolic resistance is suspected. In such patients, we propose the addition of low-dose fluvoxamine while closely monitoring clozapine levels. Based on our experience, reducing the clozapine dose by 50% and prescribing 50 mg of fluvoxamine, so as to reach a minimum effective clozapine plasma concentration of more than 350 microg/l should provide an effective therapeutic strategy. This treatment may benefit the significant number of schizophrenic patients whose response to clozapine is hindered by metabolic hyper inductivity. Although this strategy may carry some risks for certain patients, the protocol we propose reduces the latter and the potential benefits should outweigh them.

Topics: Adult; Antipsychotic Agents; Brain; Clozapine; Cytochrome P-450 Enzyme System; Fluvoxamine; Humans; Male; Middle Aged; Schizophrenia

Most antipsychotics were thought to induce antipsychotic action at an excess of 70% striatal dopamine D2 receptor occupancy, while the clinical dose of clozapine was reported to show less than 60% occupancy. High-dose clozapine could occupy as high as 80% of striatal dopamine D2 receptor in monkey PET studies. Although the time course of dopamine D2 receptor occupancy is an important property of antipsychotics, that by clozapine has not been investigated in a clinical setting. We measured the time course of extrastriatal dopamine D2 receptor occupancy with different doses of clozapine and evaluated whether the measured occupancies fitted the binding theory. Three consecutive PET scans with [11C]FLB 457 were performed for two patients with schizophrenia, chronically taking 600 mg/day and 200 mg/day of clozapine, respectively. Series of occupancies were also measured in combination with fluvoxamine or paroxetine in one patient. Dopamine D2 receptor occupancies were also simulated using individual clozapine plasma data and previously determined in vivo ED50 value. The occupancy of one patient with high plasma concentration (1207 ng/ml at peak time) was around 75% at peak and around 60% after 26 h. Another patient with medium plasma concentration (649 ng/ml at peak time) showed less than 50% occupancy at peak, decreasing to 15% after 25 h. The measured occupancy values fitted well with the simulated occupancy values. At high plasma concentration, clozapine can induce high extrastriatal dopamine D2 receptor occupancy in the human brain, and this finding fitted well with the theoretical estimation.

Topics: Adult; Antipsychotic Agents; Carbon Isotopes; Chromatography, High Pressure Liquid; Clozapine; Computer Simulation; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Electrochemistry; Fluvoxamine; Humans; Male; Paroxetine; Positron-Emission Tomography; Pyrrolidines; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Time Factors

Topics: Adult; Alleles; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Cytochrome P-450 CYP2D6; Depression; Female; Fluvoxamine; Humans; Male; Olanzapine; Pharmacogenetics; Polymorphism, Genetic; Prolactin; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Schizophrenia

The effect of amitriptyline on hypothalamic-pituitary-adrenocortical (HPA) axis activity was compared with that of fluvoxamine in 38 patients suffering from DMS-IV major depressive disorder. Basal plasma adrenocorticotropic hormone and cortisol levels were determined in the so-called "observation window" of an hour (08:00-09:00 h), and cortisol levels were determined again at 20:00 h. Clinical and biochemical assessments were performed before therapy (T0), at day 14 (T14), and at day 42 (T42) of the course of antidepressant treatment. At T0, neuroendocrine parameters did not differ in patients from those in controls, except for the ratio between cortisol levels at 20:00 h and the mean level of the "window" (ratio F20/F8), which was significantly higher, suggesting a dysregulation of the circadian pattern of cortisol. Although a decrease in the ratio F20/F8 was already apparent at T14 of both treatments, the repeated measures analysis of variance failed to demonstrate a significant variation with time (T0, T14, and T42) and with treatment (amitriptyline and fluvoxamine) for any hormonal measure. At T42, both treated groups showed a similar level of clinical improvement. Our results did not demonstrate any effect of antidepressant therapy on the cortisol circadian rhythm abnormality.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Amitriptyline; Circadian Rhythm; Depressive Disorder, Major; Diagnostic and Statistical Manual of Mental Disorders; Female; Fluvoxamine; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Pituitary-Adrenal System; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Topics: Adult; Antipsychotic Agents; Drug Administration Schedule; Drug Therapy, Combination; Fatal Outcome; Female; Fluvoxamine; Humans; Intellectual Disability; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Thioridazine

A 59-year-old man, who was being trieated for schizophrenia, exhibited a concurrence of obsessive compulsive (OC) symptoms and neuroleptics-induced deficit syndrome (NIDS). His symptoms were remarkably improved by the discontinuation of neuroleptics followed by the introduction of fluvoxamine. He was originally a prudent, suspicious and unsociable person, the character of which corresponds to a schizotypal personality disorder. From his early twenties OC-symptoms appeared along the theme of cleanliness, health, and ethics. After the first half of his forties OC-symptoms worsened with the emergence of a depressive state. He consulted a psychiatric unit at the age of 49 for the first time and was diagnosed as having schizophrenia of a negative symptoms-dominant type associated with obsessive-compulsive disorder. He was started on haloperidol but the condition did not improved at all so that the dose was gradually increased. When he finally moved to our hospital at the age of 57, serious NIDS such as slow thinking, difficulty in concentration, decrease in emotional reaction, and dysphoria was recognized, in addition to parkinsonism. In order to improve the NIDS, we gradually decreased the dose and reduced the variety of neuroleptics and substituted them for risperidone alone. During these periods, no emergence of psychotic symptoms or worsening of OC-symptoms was realized. Accordingly he was admitted to our hospital and started on fluvoxamine, and the NIDS and OC-symptoms were markedly improved. In conclusion the use of neuroleptics specifically for OC-symptoms should be done very carefully in consideration of the possibility of provoking NIDS.

Topics: Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Fluvoxamine; Haloperidol; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Personality Disorders; Risperidone; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

The effect of fluvoxamine on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was investigated in 11 schizophrenic patients with prevailingly negative or depressive symptoms. Additional fluvoxamine, at the dose of 100 mg/day, was administered for 4 weeks to patients stabilized on risperidone (3-6 mg/day). Mean plasma concentrations of risperidone, 9-OH-risperidone and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) were not significantly modified following co-administration with fluvoxamine. After 4 weeks, fluvoxamine dosage was increased to 200 mg/day in five patients and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the six patients who were still receiving the initial fluvoxamine dose, while concentrations increased slightly but significantly (by a mean 26% over pretreatment; P < 0.05) in the subgroup of five subjects treated with a final dose of 200 mg/day. Fluvoxamine co-administration with risperidone was well tolerated and no patient developed extrapyramidal side effects. These findings indicate that fluvoxamine at dosages up to 100 mg/day is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of fluvoxamine may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of fluvoxamine on CYP2D6-and/or CYP3A4-mediated 9-hydroxylation of risperidone.

Topics: Adult; Antipsychotic Agents; Cytochrome P-450 CYP2D6 Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Female; Fluvoxamine; Humans; Male; Middle Aged; Risperidone; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Topics: Anti-Anxiety Agents; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Fluvoxamine; Humans; Schizophrenia

Not enough is known about the propensity of individual negative symptoms to respond to treatment and the dynamics of this change. We have previously shown that adding the selective serotonin reuptake inhibitor fluvoxamine to antipsychotics can improve negative symptoms, and now provide data on the response of individual negative symptoms to such treatment. We examined items on the Schedule for the Assessment of Negative Symptoms for patients participating in two published controlled studies comparing the effect of add-on fluvoxamine and placebo on negative symptoms. Using a mixed regression model, we analysed item scores at each week of the study to identify the first signs of a treatment effect. Potential confounding effects of depressive extrapyramidal and positive symptoms were statistically controlled. Eleven of 16 items tested showed improvement, five within 2 weeks and a further four within 3 weeks of starting treatment. The most rapidly responding items included core negative symptoms such as alogia. The propensity for and rate of improvement with fluvoxamine treatment differs for the various negative symptoms. Many symptoms, including those generally agreed to be core features of the illness such as alogia, improved within 2-3 weeks of treatment initiation.

Topics: Antipsychotic Agents; Aphasia; Chronic Disease; Clinical Trials as Topic; Data Interpretation, Statistical; Drug Administration Schedule; Drug Therapy, Combination; Fluvoxamine; Humans; Regression Analysis; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Time Factors; Treatment Outcome

Establishing that treatment for negative symptoms improves primary features of schizophrenia rather than similar symptoms of other etiology is an important clinical issue. Primary negative symptoms may also differ among themselves in the propensity to respond to a given treatment. In this study, we examined the response of negative symptoms to add-on fluvoxamine by analyzing discrete symptoms independently and controlling for potential confounding variables. Data from two published controlled studies comparing fluvoxamine to placebo were pooled for the analysis. Eleven of sixteen Scale for the Assessment of Negative Symptoms items tested, including key negative symptoms such as affective flattening and alogia, improved. The improvement was not related to baseline levels of depressive, extrapyramidal, and positive symptoms or to changes in the symptom scores during the study. The findings support the view that fluvoxamine augmentation can improve primary negative symptoms in chronic schizophrenia patients.

Topics: Affect; Antipsychotic Agents; Chronic Disease; Diagnostic and Statistical Manual of Mental Disorders; Drug Synergism; Female; Fluvoxamine; Humans; Male; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Topics: Adolescent; Dopamine Antagonists; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Obsessive-Compulsive Disorder; Risperidone; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Dysfunction of monoamine neurotransmission seems to contribute to such pathopsychological states as depression, schizophrenia, and drug abuse. The present study examined the effects of the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and antidepressant fluvoxamine on locomotor activity in rats following administration of the catecholamine reuptake inhibitor mazindol. Mazindol (1 mg/kg) did not alter locomotor activity; whereas, fluvoxamine (20 mg/kg) given alone induced a brief period of hypomotility. Hyperactivity was elicited in a dose-related manner when fluvoxamine (5-20 mg/kg) was combined with mazindol (1 mg/kg). The hyperactivity elicited by fluvoxamine (20 mg/kg) plus mazindol (1 mg/kg) was significantly attenuated by the 5-HT(2A) receptor antagonist M100907 (2 mg/kg) and potentiated by the 5-HT(2B/2C) receptor antagonist SB 206553 (2 mg/kg). Neither antagonist significantly altered basal activity. The hyperactivity evoked by the combination of fluvoxamine and mazindol seems to be mediated in part by 5-HT(2A) receptors; whereas, 5-HT(2B/2C) receptors may serve to limit this effect. Thus, the balance of activation between 5-HT(2A) and 5-HT(2B/2C) receptors seems to contribute to the expression of locomotor hyperactivity evoked via combination of a 5-HT and a catecholamine reuptake inhibitor. A disruption in this balance may contribute to the expression of affective disorders, schizophrenia, and drug abuse.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Biogenic Monoamines; Catecholamines; Depression; Dopamine; Drug Synergism; Fluorobenzenes; Fluvoxamine; Indoles; Male; Mazindol; Motor Activity; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin; Substance-Related Disorders

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Drug Therapy, Combination; Fluvoxamine; Humans; Male; Obsessive-Compulsive Disorder; Olanzapine; Pirenzepine; Polypharmacy; Priapism; Risperidone; Schizophrenia; Treatment Outcome

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Depressive Disorder; Drug Interactions; Female; Fluvoxamine; Humans; Olanzapine; Pirenzepine; Schizophrenia

Topics: Adult; Anticonvulsants; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Carbamazepine; Drug Interactions; Drug Therapy, Combination; Fluvoxamine; Humans; Male; Risperidone; Schizophrenia

Concomitant fluvoxamine use can potentially reduce the dosage of clozapine needed in treatment-refractory patients with schizophrenia. Previous reports have shown that fluvoxamine can increase plasma clozapine concentrations by inhibition of cytochrome P450 (CYP) 1A2. We evaluated the safety and efficacy of fluvoxamine, 50 mg/day, coadministration with clozapine, 100 mg/day, in refractory schizophrenic patients.. In this prospective study, 18 treatment-refractory patients with DSM-IV schizophrenia (10 nonsmokers and 8 smokers) were treated with clozapine at a target dose of 100 mg h.s. After steady-state conditions of clozapine had been reached, 50 mg/day of fluvoxamine was then added. Plasma levels of clozapine, norclozapine, and clozapine N-oxide were measured prior to fluvoxamine addition and on days 14 and 28 during combined treatment. Side effects and efficacy were monitored with standardized rating instruments.. After 14 days of combined treatment, the mean +/- SD plasma clozapine level increased 2.3-fold to 432.4+/-190.9 ng/mL without further elevation on day 28. All patients completed the study without significant adverse side effects. Twelve of the 18 patients achieved plasma clozapine concentrations of at least 350 ng/mL. While plasma norclozapine levels also rose (but to a smaller extent), plasma clozapine N-oxide levels remained unchanged after the add-on therapy. Patients who smoked had 34% lower plasma clozapine concentrations than nonsmokers (NS). Three of the 4 patients who did not reach clozapine plasma levels of at least 300 ng/mL were smokers. Plasma norclozapine/clozapine ratios, especially in smokers, declined significantly with fluvoxamine addition.. The addition of fluvoxamine, 50 mg/day, to low-dose clozapine, 100 mg/day, can raise plasma clozapine levels to at least 300 ng/mL in most patients. Only slight dosage adjustments with clozapine may be needed after fluvoxamine coadministration in some patients who smoke. Plasma clozapine levels remained stable after 14 days of fluvoxamine addition. The combined treatment was well tolerated, and clinical improvement was observed in our patients. Further long-term studies with this drug combination are needed to determine its economic impact.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Comorbidity; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Smoking; Treatment Outcome

Topics: Adult; Analysis of Variance; Clozapine; Dose-Response Relationship, Drug; Drug Interactions; Female; Fluvoxamine; Humans; Male; Middle Aged; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists

The drug-drug interaction between fluvoxamine (FLV) and clozapine (CLZ) was evaluated by in-vitro and in-vivo methods. In-vitro studies were conducted using human hepatic microsomal preparations with standard chemical inhibitors of the cytochrome P450 (CYP 450) isozyme system. Furafyline, FLV, troleandomycin (TAO) and erythromycin were used as the chemical inhibitors. For the in-vivo study, nine male schizophrenic patients were administered a single dose of CLZ 50 mg on two separate occasions with a 2-week FLV treatment of 50 mg twice a day in between each CLZ dose. Blood samples were obtained over 48 h following CLZ administration. CLZ and its two principle metabolites, clozapine N-oxide (CNO) and desmethylclozapine (DCLZ), were measured by high performance liquid chromatography with ultraviolet detection for both in-vitro and in-vivo studies. The in-vitro formation of DCLZ was inhibited by furafyline and FLV by 42.0% and 48.5% (P<0.01), respectively. TAO and erythromycin had only modest inhibition effects on DCLZ formation of 18.3% and 21.0% (P = NS), respectively. CNO in-vitro formation was significantly reduced by TAO and erythromycin by 44.5% and 45.0% (P<0.01), respectively. Furafyline and FLV had only modest effects of 19.2% and 8.5% (P = NS), respectively. In schizophrenic patients, FLV resulted in a pronounced increased in CLZ plasma concentrations with the total mean CLZ AUC increased by a factor of 2.58 from 780.8 ng/ml per hour to 2218.0 ng/ml per hour (P<0.001). All patients were sedated during combined FLV and CLZ use. During FLV treatment, CNO and DCLZ AUC both decreased by 18.8% (P = 0.07) and 9.0% (P = NS), respectively. These results indicate that in-vitro evaluations may not always accurately reflect changes in drug-drug interaction observed in-vivo. Careful patient monitoring is recommended during FLV/CLZ co-administration.

Topics: Adult; Anti-Anxiety Agents; Antipsychotic Agents; Area Under Curve; Clozapine; Drug Interactions; Fluvoxamine; Humans; Male; Microsomes, Liver; Middle Aged; Schizophrenia

This study investigated to what extent fluvoxamine affects the pharmacokinetics of thioridazine (THD) in schizophrenic patients under steady-state conditions. Concentrations of THD, mesoridazine, and sulforidazine were measured in plasma samples obtained from 10 male inpatients, aged 36 to 78 years, at three different time points: A, during habitual monotherapy with THD at 88 +/-54 mg/day; B, after addition of a low dosage of fluvoxamine (25 mg twice a day) for 1 week; and C, 2 weeks after fluvoxamine discontinuation. After the addition of fluvoxamine, THD concentrations relative to time point A significantly increased approximately threefold from 0.40 to 1.21 micromol/L (225%) (p < 0.002), mesoridazine concentrations increased from 0.65 to 2.0 micromol/L (219%) (p < 0.004), and sulforidazine levels increased from 0.21 to 0.56 micromol/L (258%) (p < 0.004). The THD-mesoridazine and THD-sulforidazine ratios remained unchanged during the study. Mean plasma THD, mesoridazine, and sulforidazine levels decreased at time point C, but despite fluvoxamine discontinuation for 2 weeks, three patients continued to exhibit elevated concentrations of THD and its metabolites. In conclusion, fluvoxamine markedly interferes with the metabolism of THD, probably at the CYP2C19 and/or CYP1A2 enzyme level. Therefore, clinicians should be aware of the potential for a clinical drug interaction between both compounds, and careful monitoring of THD levels is valuable to prevent the accumulation of the drug and resulting toxicity.

Topics: Adult; Aged; Antipsychotic Agents; Cytochrome P-450 CYP2D6; Drug Interactions; Fluvoxamine; Humans; Male; Mesoridazine; Middle Aged; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Thioridazine

Topics: Adult; Aggression; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Risperidone; Schizophrenia; Schizophrenic Psychology

Deliberate drug overdose is a frequent occurrence in patients with schizophrenia. Typical antipsychotic medications can be lethal at doses 5 times the recommended therapeutic range. Clozapine, an atypical antipsychotic, can be toxic at doses 4 times a moderate dose. Little is known about the lethal effects of the novel antipsychotic risperidone, despite the fact that it is now one of the most widely prescribed antipsychotics in North America. To date, only 1 death attributable to risperidone overdose has been reported. The case presented here documents adverse cardiac effects in a 28-year-old man who intentionally ingested 24 mg of risperidone--4 times the recommended dose. A potential drug interaction with fluvoxamine and the role of active metabolites are discussed.

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Drug Interactions; Drug Overdose; Electrocardiography; Fluvoxamine; Heart Block; Humans; Hypotension; Male; Risperidone; Schizophrenia; Suicide, Attempted

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Drug Interactions; Female; Fluvoxamine; Humans; Male; Middle Aged; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fluvoxamine; Humans; Male; Schizophrenia; Schizophrenic Psychology; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Topics: Adult; Clozapine; Drug Interactions; Female; Fluvoxamine; Humans; Male; Middle Aged; Schizophrenia

Topics: Adult; Biomarkers; Chronic Disease; Dose-Response Relationship, Drug; Drug Tolerance; Female; Fluvoxamine; Humans; Male; Melatonin; Psychiatric Status Rating Scales; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Interest in the association of obsessive-compulsive (OC) symptoms and schizophrenia has been reawakened since the introduction of clozapine for treatment of schizophrenia. We describe the appearance of this disorder and examine the efficacy of adding fluvoxamine to ongoing clozapine treatment of the OC and schizophrenic symptoms. Four patients with DSM-III-R schizophrenic disorder, in whom OC symptoms appeared during the course of clozapine treatment, are reported. In two patients, fluvoxamine, a serotonin-selective reuptake inhibitor (SSRI), was added to clozapine under open-trial conditions. The patients were serially assessed by using the Brief Psychiatric Rating Scale, Yale-Brown Obsessive-Compulsive Scale, and Scale for the Assessment of Negative Symptoms. The de novo occurrence and eventual spontaneous reduction of OC symptoms were noted in two schizophrenic patients treated with clozapine. In the other two patients, one with previous and the other with a family history of OC disorder, the addition of fluvoxamine to clozapine was effective in eliminating the OC symptoms. A concomitant improvement in the schizophrenic symptomatology was seen as well. It appears that disabling OC symptoms may occur as in response to clozapine treatment in chronic drug-resistant schizophrenic patients. Some of the latter may benefit from the addition of an SSRI to the ongoing clozapine regimen.

Topics: Adult; Clozapine; Fluvoxamine; Humans; Male; Obsessive-Compulsive Disorder; Schizophrenia

In this case report we describe an interaction between clozapine and fluvoxamine in two physically healthy patients meeting the DSM-IIIR criteria for paranoid schizophrenia. The substantial rise of clozapine serum levels suggest that caution should be exercised when combining fluvoxamine with clozapine as the clozapine concentration may increase by a factor of 5-10.

Topics: Adult; Clozapine; Drug Interactions; Fluvoxamine; Humans; Male; Schizophrenia

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Male; Middle Aged; Pilot Projects; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Adult; Bulimia; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Obsessive-Compulsive Disorder; Schizophrenia

Topics: Adult; Female; Fluvoxamine; Humans; Male; Psychoses, Substance-Induced; Schizophrenia; Selective Serotonin Reuptake Inhibitors

Topics: Adult; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Fluvoxamine; Humans; Male; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Antipsychotic Agents; Drug Therapy, Combination; Fluvoxamine; Humans; Isoxazoles; Male; Obsessive-Compulsive Disorder; Piperidines; Receptors, Serotonin; Risperidone; Schizophrenia; Schizophrenic Psychology; Serotonin

Topics: Depressive Disorder; Female; Fluvoxamine; Humans; Middle Aged; Schizophrenia

Two cases of alopecia observed during treatment with lithium and valproate are described, and the recent literature on this subject is reviewed. Our clinical observations confirm earlier reports. These toxic alopecias are characterized by a diffuse but rarely total hair loss. After stopping medication, the hair grows back generally and completely. Two cases of toxic alopecia are presented where hair grew back following a substitution of lithium by valproate in the first case and after stopping valproate in the second. The evaluation and therapeutic attitude in the presence of alopecia in patients needing mood stabilizers are also discussed.

Topics: Adult; Alopecia; Carbamazepine; Clorazepate Dipotassium; Depressive Disorder; Female; Fluvoxamine; Haloperidol; Hospitalization; Humans; Lithium Carbonate; Methotrimeprazine; Middle Aged; Schizophrenia; Valproic Acid