fluvoxamine and nefazodone

Sleep disturbances are among the most commonly endorsed symptoms of post-traumatic stress disorder (PTSD). Treatment modalities that are effective for the waking symptoms of PTSD may have limited efficacy for post-traumatic sleep problems. The aim of this review is to summarize the evidence for empirically supported and/or utilized psychotherapeutic and pharmacological treatments for post-traumatic nightmares and insomnia. While there are few controlled studies of the applicability of general sleep-focused interventions to the management of the sleep disturbances in PTSD, evidence is growing to support several psychotherapeutic and pharmacological treatments. Future investigations should include trials that combine treatments focused on sleep with treatments effective in managing the waking symptoms of PTSD.

Topics: Antipsychotic Agents; Cognitive Behavioral Therapy; Dreams; Eye Movement Desensitization Reprocessing; Fluvoxamine; Humans; Piperazines; Prazosin; REM Sleep Behavior Disorder; Restless Legs Syndrome; Serotonin and Noradrenaline Reuptake Inhibitors; Sleep; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders; Stress Disorders, Post-Traumatic; Trazodone; Triazoles

Medication treatment studies have demonstrated short-term efficacy of various SRIs, opioid antagonists, and mood stabilizers in sub-samples of adult treatment seeking pathological gamblers. Pathological gambling is frequently comorbid with bipolar spectrum disorders, substance abuse/dependence, and attention-deficit/hyperactivity disorder (ADHD), and comorbidity may influence treatment response in pathological gambling. This review focuses on recent research examining the treatment of pathological gambling and highlights methodological challenges for future studies.

Topics: Antidepressive Agents, Second-Generation; Behavior, Addictive; Bupropion; Comorbidity; Disruptive, Impulse Control, and Conduct Disorders; Dose-Response Relationship, Drug; Fluvoxamine; Gambling; Humans; Naltrexone; Outcome Assessment, Health Care; Paroxetine; Piperazines; Research Design; Selective Serotonin Reuptake Inhibitors; Substance-Related Disorders; Triazoles

Seven of the newest antidepressants are the serotonin selective reuptake inhibitors (fluoxetine, sertraline, paroxetine, and fluvoxamine [currently approved in the United States for obsessive-compulsive disorder only]), a serotonin norepinephrine reuptake inhibitor (venlafaxine), a postsynaptic serotonin antagonist/presynaptic serotonin reuptake inhibitor (nefazodone), and presynaptic/postsynaptic noradrenergic/serotonergic receptor antagonist (mirtazapine). Many of these drugs are potent inhibitors of the cytochrome P450 (CYP) enzymes of the liver. The CYP enzymes most relevant to the use of antidepressants and for which the most thorough data are available are the CYP1A2, CYP2D6, and CYP3A4. These 3 CYP isoenzymes are discussed in relation to some of the drugs they metabolize, and appropriate cautions are recommended for concurrent administration of these new antidepressants and other drugs frequently prescribed to elderly patients.

Topics: Antidepressive Agents; Cyclohexanols; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Depressive Disorder; Drug Interactions; Drug Therapy, Combination; Fluoxetine; Fluvoxamine; Humans; Mixed Function Oxygenases; Piperazines; Selective Serotonin Reuptake Inhibitors; Triazoles; Venlafaxine Hydrochloride

Topics: Antidepressive Agents; Antidepressive Agents, Second-Generation; Depressive Disorder; Fluvoxamine; Humans; Piperazines; Triazoles

Inhibitors of steroid synthesis have been reported to exert antidepressive effects, according to preliminary findings.. To test whether the addition of metyrapone to standard antidepressants induces a more rapid, more efficacious, and sustained treatment response in patients with major depression.. Double-blind, randomized, placebo-controlled trial.. Hospitalized care.. Sixty-three inpatients with a DSM-IV diagnosis of major depression and a baseline score 18 points or higher on the Hamilton Rating Scale for Depression.. Random allocation to 2 treatment groups receiving either placebo or metyrapone (1 g/d) for the first 3 weeks during a 5-week treatment with standard serotonergic antidepressants (nefazodone or fluvoxamine).. Primary outcome criteria were the number of responders and the time to onset of action. Responder rates were considered twice after 3 and 5 weeks with a definition of treatment response as 30% and 50% reduction, respectively, of baseline Hamilton Rating Scale for Depression scores. Onset of action was defined as the time point at which at least a 20% reduction of baseline Hamilton Rating Scale for Depression scores occurred.. Using intention-to-treat analysis, we found that a higher proportion of patients receiving metyrapone showed a positive treatment response at day 21 (23 of 33 patients) and at day 35 (19 of 33 patients) compared with placebo patients (day 21: 13 of 30 patients; Fisher exact P = .031; day 35: 10 of 30 patients; Fisher exact P = .047). The clinical course of patients treated with metyrapone showed an earlier onset of action (Kaplan-Meier analysis; log-rank test P<.006) beginning in the first week. The plasma concentrations of corticotropin and deoxycortisol were significantly higher during metyrapone treatment (multivariate analysis of covariance, P<.05), whereas cortisol remained largely unchanged. Metyrapone treatment was well tolerated without serious adverse effects.. Metyrapone is an effective adjunct in the treatment of major depression, accelerating the onset of antidepressant action. A better treatment outcome compared with standard treatment and a sustained antidepressive effect were observed.

Topics: Adrenocorticotropic Hormone; Adult; Antidepressive Agents; Cortodoxone; Dehydroepiandrosterone; Depressive Disorder, Major; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Female; Fluvoxamine; Humans; Male; Metyrapone; Middle Aged; Piperazines; Placebos; Psychiatric Status Rating Scales; Treatment Outcome; Triazoles

The objective of this study was to investigate pharmacokinetic and pharmacodynamic interactions between midazolam and fluoxetine, fluvoxamine, nefazodone, and ketoconazole. Forty healthy subjects were randomized to receive one of the four study drugs for 12 days in a parallel study design: fluoxetine 60 mg per day for 5 days, followed by 20 mg per day for 7 days; fluvoxamine titrated to a daily dose of 200 mg; nefazodone titrated to a daily dose of 400 mg; or ketoconazole 200 mg per day. All 40 subjects received oral midazolam solution before and after the 12-day study drug regimen. Blood samples for determination of midazolam concentrations were drawn for 24 hours after each midazolam dose and used for the calculation of pharmacokinetic parameters. The effects of the study drugs on midazolam pharmacodynamics were assessed using the symbol digit modalities test (SDMT). The mean area under the curve (AUC) for midazolam was increased 771.9% by ketoconazole and 444.0% by nefazodone administration. However, there was no significant change in midazolam AUC as a result of fluoxetine (13.4% decrease) and a statistical trend for fluvoxamine (66.1% increase) administration. Pharmacodynamic data are consistent with pharmacokinetic data indicating that nefazodone and ketoconazole resulted in significant increases in midazolam-related cognition impairment. The significant impairment in subjects' cognitive function reflects the changes in midazolam clearance after treatment with ketoconazole and nefazodone. These results suggest that caution with the use of midazolam is warranted with potent CYP3A4 inhibitors.

Topics: Administration, Oral; Adult; Analysis of Variance; Area Under Curve; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Female; Fluoxetine; Fluvoxamine; Humans; Ketoconazole; Male; Midazolam; Piperazines; Triazoles

The Davidson Trauma Scale (DTS) is a validated 17-item self-rating scale used in the diagnosis of post-traumatic stress disorder (PTSD), which is sensitive to the effects of treatment. It was felt that a shorter version of the scale might provide a better diagnostic screening tool. Subjects were drawn from a sample of 243 patients obtained from multiple cohorts that included a group of survivors of various forms of trauma, including natural disaster, rape and combat. All subjects had diagnostic assessments for PTSD with a clinical interview and completed the DTS. The data were randomly divided between two subsamples, and frequency and severity scores were calculated for the DTS. A four-item scale, the SPAN (named for its top four items: Startle, Physiological arousal, Anger, and Numbness), was developed. It demonstrated an efficiency of 0.88, sensitivity of 0.84, specificity of 0.91 and positive likelihood ratio of 9.1. In a replication sample, values were slightly lower but still acceptable (efficiency = 0.80). A subgroup of PTSD patients received either fluoxetine or placebo in a clinical trial, and a significant SPAN score improvement was observed on fluoxetine. The SPAN, which correlated significantly with the Impact of Events Scale, the Sheehan Disability Scale, and the Structured Interview of PTSD, was found to have a diagnostic accuracy of 88%.

Topics: Adult; Antidepressive Agents; Cohort Studies; Combat Disorders; Disasters; Female; Fluoxetine; Fluvoxamine; Humans; Lamotrigine; Male; Middle Aged; Personality Inventory; Piperazines; Psychometrics; Rape; Reproducibility of Results; Stress Disorders, Post-Traumatic; Triazines; Triazoles

The intravaginal ejaculation latency time (IELT) behaves in a skewed manner and needs the appropriate statistics for correct interpretation of treatment results.. To explain the rightful use of geometrical mean IELT values and the fold increase of the geometric mean IELT because of the positively skewed IELT distribution.. Linking theoretical arguments to the outcome of several selective serotonin reuptake inhibitor and modern antidepressant study results.. Geometric mean IELT and fold increase of geometrical mean IELT.. Log-transforming each separate IELT measurement of each individual man is the basis for the calculation of the geometric mean IELT. A drug-induced positively skewed IELT distribution necessitates the calculation of the geometric mean IELTs at baseline and during drug treatment. In a positively skewed IELT distribution, the use of the "arithmetic" mean IELT risks an overestimation of the drug-induced ejaculation delay as the mean IELT is always higher than the geometric mean IELT. Strong ejaculation-delaying drugs give rise to a strong positively skewed IELT distribution, whereas weak ejaculation-delaying drugs give rise to (much) less skewed IELT distributions. Ejaculation delay is expressed in fold increase of the geometric mean IELT.. Drug-induced ejaculatory performance discloses a positively skewed IELT distribution, requiring the use of the geometric mean IELT and the fold increase of the geometric mean IELT.

Topics: Antidepressive Agents; Coitus; Data Interpretation, Statistical; Ejaculation; Fluoxetine; Fluvoxamine; Humans; Male; Mianserin; Mirtazapine; Models, Biological; Piperazines; Reaction Time; Research Design; Selective Serotonin Reuptake Inhibitors; Sensitivity and Specificity; Sertraline; Sexual Dysfunction, Physiological; Treatment Outcome; Triazoles

The selective serotonin (5-HT) reuptake inhibitors (SSRIs) represent the first-line pharmacotherapy for obsessive-compulsive disorder (OCD), and atypical antipsychotic drugs, which block 5-HT2A receptors, are used in augmentation strategies. Opiate drugs are also effective in treatment-refractory OCD and Tourette syndrome. The 5-HT2A-related behavior (i.e., head twitch) has been related with tics, stereotypes, and compulsive symptoms observed in Tourette syndrome and OCD.. The aim of this study was to explore whether 5-HT2A-related behavior is affected by atypical opiate drugs.. Head-twitch response was induced in mice by administration of either 5-hydroxytryptophan (5-HTP) or the 5-HT2A/C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Dose-effect curves of atypical opiate drugs [(+/-)-tramadol, (-)-methadone and levorphanol], morphine, and other psychoactive drugs (fluvoxamine, desipramine, nefazodone, and clozapine) were performed. Opioid mechanisms were investigated by administration of naloxone.. All the opiates tested reduced both 5-HTP and DOI-induced behavior in a naloxone-reversible fashion, atypical opiates being more effective. The effects of the other drugs depended on the protocol, clozapine being the most effective.. Combined 5-HT and opioid properties result in a greater efficacy in antagonizing 5-HT2A-related behavior. These results provide behavioral evidence to support convergent effects of the 5-HT and opioid systems in discrete brain areas, offering the potential for therapeutic advances in the management of refractory stereotypes and compulsive behaviors.

Topics: 5-Hydroxytryptophan; Analgesics, Opioid; Animals; Clozapine; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Fluvoxamine; Indophenol; Levorphanol; Male; Methadone; Mice; Morphine; Naloxone; Narcotic Antagonists; Obsessive-Compulsive Disorder; Piperazines; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Stereotyped Behavior; Tics; Tourette Syndrome; Tramadol; Triazoles

The in vitro biotransformation of bupropion to hydroxybupropion was studied in human liver microsomes and microsomes containing heterologously expressed human cytochromes P450 (CYP). The mean (+/-S.E.) K(m) in four human liver microsomes was 89 (+/-14) microM. In microsomes containing cDNA-expressed CYPs, hydroxybupropion formation was mediated only by CYP2B6 at 50 microM bupropion (K(m) 85 microM). A CYP2B6 inhibitory antibody produced more than 95% inhibition of bupropion hydroxylation in four human livers. Bupropion hydroxylation activity at 250 microM was highly correlated with S-mephenytoin N-demethylation activity (yielding nirvanol), another CYP2B6-mediated reaction, in a panel of 32 human livers (r = 0.94). The CYP2B6 content of 12 human livers highly correlated with bupropion hydroxylation activity (r = 0.96). Thus bupropion hydroxylation is mediated almost exclusively by CYP2B6 and can serve as an index reaction reflecting activity of this isoform. IC(50) values for inhibition of a CYP2D6 index reaction (dextromethorphan O-demethylation) by bupropion and hydroxybupropion were 58 and 74 microM, respectively. This suggests a low inhibitory potency versus CYP2D6, the clinical importance of which is not established. Since bupropion is frequently coadministered with other antidepressants, IC(50) values (microM) for inhibition of bupropion hydroxylation were determined as follows: paroxetine (1.6), fluvoxamine (6.1), sertraline (3.2), desmethylsertraline (19.9), fluoxetine (59.5), norfluoxetine (4.2), and nefazodone (25.4). Bupropion hydroxylation was only weakly inhibited by venlafaxine, O-desmethylvenlafaxine, citalopram, and desmethylcitalopram. The inhibition of bupropion hydroxylation in vitro by a number of newer antidepressants suggests the potential for clinical drug interactions.

Topics: Antibodies; Antidepressive Agents, Second-Generation; Aryl Hydrocarbon Hydroxylases; Biotransformation; Bupropion; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2B6; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Fluoxetine; Fluvoxamine; Humans; Hydroxylation; Isoenzymes; Kinetics; Microsomes, Liver; Oxidoreductases, N-Demethylating; Paroxetine; Piperazines; Sertraline; Triazoles

Given their equal efficacy, the choice of a specific antidepressant is largely influenced by side effect (SE) profiles. A number of new agents have recently become available. However, data directly comparing the side effects of these agents are scarce. As suggested by AHCPR guidelines, we used the 1998 Physicians' Desk Reference (PDR) to construct a comparison table using treatment emergent, placebo-adjusted incidence rates for the major (gastrointestinal, central nervous system, and sexual) side effects caused by nine antidepressants (fluoxetine, paroxetine, sertraline, fluvoxamine, nefazodone, bupropion SR, mirtazapine, venlafaxine XR, and citalopram). The results were tabulated to show the relative propensity of each drug to cause a particular side effect. Bupropion SR had the most favorable overall side-effect profile, and fluvoxamine the least favorable. However, there are several limitations in using the PDR to compare the newer antidepressants. Clinical studies directly comparing SEs of newer antidepressants are needed. Sexual SEs substantially affected total SE liability. A simplified summary table, with its advantages and some limitations, is not simple to construct. Pitfalls in this process are discussed.

Topics: Antidepressive Agents; Bupropion; Central Nervous System Diseases; Citalopram; Cyclohexanols; Delayed-Action Preparations; Drug Information Services; Fluvoxamine; Gastrointestinal Diseases; Guidelines as Topic; Humans; Incidence; Paroxetine; Piperazines; Placebos; Selective Serotonin Reuptake Inhibitors; Sertraline; Sexual Dysfunctions, Psychological; Triazoles; United States; United States Agency for Healthcare Research and Quality; Venlafaxine Hydrochloride

The favorable safety profile of the newer antidepressant drugs recently introduced has lead to their increased use in transplant recipients. These new agents are a chemically diverse group of compounds that have selective serotonin reuptake inhibitory properties. Most of these medications inhibit one or more hepatic microsomal cytochrome p450 isoenzymes. Because cyclosporine is metabolized predominantly by CYP3A3/4 isoenzymes, inhibition of this system can lead to the buildup of toxic levels. Two case reports of cyclosporine toxicity attributable to interactions with the novel antidepressants nefazodone and fluvoxamine are presented. The serum creatinine and whole blood cyclosporine levels were found to be elevated at a routine clinic visit. Although it was subsequently possible to reduce the dose of cyclosporine by between 33% and 50%, the frequency of blood draws and consultations was greatly increased in both patients over several weeks, resulting in considerable patient anxiety. Interestingly, both nefazodone and fluvoxamine are known to potently inhibit the CYP3A3/4 isoenzymes. It is concluded that the introduction of a novel antidepressant to a cyclosporine-treated allograft recipient may be complicated by cyclosporine toxicity. Intensive monitoring of the serum creatinine and cyclosporine level is indicated under such circumstances, with dose reductions performed as indicated.

Topics: Antidepressive Agents, Second-Generation; Cyclosporine; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Female; Fluvoxamine; Humans; Kidney Transplantation; Male; Middle Aged; Piperazines; Selective Serotonin Reuptake Inhibitors; Triazoles