Bupropión: farmacología e interacciones / Bupropion: pharmacology and interactions

Bupropión es una aminocetona monocíclica introducida en España para el tratamiento de la depresión en la formulación XR/XL de liberación modificada que permite su administración en una única toma diaria. Se metaboliza en su principal metabolito activo, el hidroxibupropión (OHBUP) por el citocromo P450 2B6 (CYP2B6), teniendo una vida media de eliminación de alrededor de 20 h. Es un inhibidor de la recaptación de la noradrenalina y la dopamina, con un efecto sobre el transportador de serotonina prácticamente nulo. Presenta una baja (12-35%), pero persistente ocupación del transportador estriatal de dopamina. No tiene efectos clínicamente significativos sobre los receptores histaminérgicos, muscarínicos, alfa-adrenérgicos o dopaminérgicos. Las interacciones principales están relacionadas con la inhibición o inducción del CYP2B6, responsable del metabolismo del bupropión, o la inhibición del CYP2D6 por el bupropión. Se aconseja un uso cuidadoso conjuntamente con fármacos que disminuyan el umbral convulsivo. Está contraindicado durante la supresión brusca de alcohol o sedantes y durante el tratamiento con inhibidores de la monoaminooxidasa. El presente artículo responde a preguntas frecuentes que se plantean durante el uso clínico del bupropión, especialmente en situaciones clínicas especiales o durante el tratamiento con otros fármacos habituales. Estas situaciones incluyen, entre otras, uso conjunto de fármacos anticonvulsivantes, antipsicóticos en depresión psicótica, corticosteroides, antidiabéticos, otros antidepresivos como venlafaxina, anticonceptivos orales, terapia hormonal sustitutiva, disulfiram, alcohol o drogas de abuso y vareniclina (AU)

Bupropion is a monocyclic aminoketone introduced into Spain for the treatment of depression with the extended release (XL) formulation that makes it possible to administer it in a single daily dose. It is metabolized in its principal active metabolite, the hydroxybupropion (OH-BUP) by the cytochrome P450 2B6 (CYP2B6), with a mean elimination half life of about 20 h. It is a norepinephrine and dopamine reuptake inhibitor with an almost null effect on the serotonin transporter. It has low (12%-35%) but persistent occupancy of the striatal dopaminetransporter. It has no clinically significant effects on the histaminergic, muscarinic, alpha-adrenergicor domaminergic receptors. Its principal interactions are related with inhibition or induction of CYP2B6, responsible for the bupropion metabolism, or inhibition of CYP2D6 by bupropion. It should be used carefully together with drugs that decrease the seizure threshold. This is contraindicated during sudden suppression of alcohol or sedatives and during treatment with monoaminooxidade inhibitors. The present paper answers frequent questions posed during the clinical use of bupropion, especially under special clinical situations or during treatment with other common drugs. These situations include, among others, combined use of anti-seizure drugs, antipsychotics in psychotic depression, corticosteroids, antidiabetics, other antidepressants such as venlafaxin, oral contraceptives, hormone replacement hormone therapy, disulfiram, alcohol or abuse drugs and varenicline (AU)

Benzodiazepines and anticonvulsants for social phobia (social anxiety disorder).

Both benzodiazepines and conventional anticonvulsants have been evaluated as treatments for social phobia (social anxiety disorder). Among the benzodiazepines, clonazepam is the best studied, although there is reason to expect that all benzodiazepine anxiolytics would be effective for this condition. Among the anticonvulsants, gabapentin and pregabalin, an analogue of gamma-aminobutyric acid (GABA), have been shown to be more effective than placebo in double-blind studies. Other than a small negative open study of valproic acid for social phobia, there is a paucity of information on whether other anticonvulsants might be useful for this condition.

Mood stabilizers during breastfeeding: a review.

BACKGROUND: The postpartum period is an exceptionally high-risk time for recurrence of depression, mania, or psychosis for women with bipolar disorder. Puerperal prophylaxis with mood stabilizers decreases this risk. To allow patients and clinicians to make informed decisions about mood-stabilizer use during breastfeeding, there is a need for a critical review and analysis of the data. DATA SOURCES: A search of MEDLINE (1966-1998) and the Lithium Database, Madison Institute of Medicine, was conducted to obtain articles about lithium, valproate, carbamazepine, gabapentin, or lamotrigine use during lactation. Search terms used were pregnancy, teratogenesis, breastfeeding, lactation, breast milk levels and lithium, anticonvulsants, mood stabilizers. No other search restrictions were used. Unpublished data on gabapentin and lamotrigine were provided by the manufacturers. RESULTS: The search revealed 11 cases of lithium use during breastfeeding, 8 of which reported infant serum levels. Two cases reported symptoms consistent with lithium toxicity in the infants. Thirty-nine cases of valproate use during breastfeeding were found, 8 of which reported infant serum levels. There was 1 report of thrombocytopenia and anemia in an infant. Fifty cases of carbamazepine use during breastfeeding were found, 10 of which reported infant serum levels. Two infants experienced hepatic dysfunction. One unpublished study of gabapentin in breast milk was found. Three reports of lamotrigine use during breastfeeding were found. DISCUSSION: Available information remains limited to uncontrolled studies and case reports. Carbamazepine and valproate, but not lithium, have generally been considered compatible with breastfeeding. The overall paucity of data, data confounded by polypharmacy and infant age differences, and adverse reactions reported with all established mood stabilizers dictate a reassessment of these recommendations. We propose that a woman's historical response to medication and the clinical circumstances be the primary considerations when choosing a mood stabilizer during breastfeeding, rather than strict adherence to categorical assignments.

Treatment of social phobia with gabapentin: a placebo-controlled study.

A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of social phobia. Sixty-nine patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 900 and 3,600 mg daily in three divided doses) or placebo for 14 weeks. A significant reduction (p < 0.05) in the symptoms of social phobia was observed among patients on gabapentin compared with those on placebo as evaluated by clinician- and patient-rated scales. Results were similar for the intent-to-treat and week-2 completer populations. Adverse events were consistent with the known side effect profile of gabapentin. Dizziness (p = 0.05), dry mouth (p = 0.05), somnolence, nausea, flatulence, and decreased libido occurred at a higher frequency among patients receiving gabapentin than among those receiving placebo. No serious adverse events or deaths were reported. On the basis of these limited data, it seems that gabapentin offers a favorable risk-benefit ratio for the treatment of patients with social phobia. Further studies are required to confirm this effect and to determine whether a dose-response relationship exists.

Computerized assessment of depression and anxiety over the telephone using interactive voice response.

We examined the reliability and validity of computer-administered versions of the Hamilton Depression (HAMD) and Hamilton Anxiety (HAMA) Rating Scales that were administered over the telephone using Interactive Voice Response (IVR). In two identical studies (HAMD: N = 113, HAMA: N = 74), both the IVR- and clinician-administered versions were administered in a counterbalanced order to a heterogeneous sample of subjects with psychiatric disorders and controls. Both the IVR HAMD and HAMA demonstrated adequate internal-consistency reliability (.90 and .93, respectively) and test-retest reliability (.74 and .97, respectively). The correlation between the IVR and clinician was high (HAMD = .96; HAMA = .65). The mean score difference between the IVR and clinician versions was less than one point for both the HAMD (.69 of a point) and HAMA (.60 of a point). It took subjects 12.23 minutes to complete the IVR HAMD, compared to 15.21 minutes for the clinician version; and 11.27 minutes for the IVR HAMA, compared to 15.33 minutes for the clinician (p < .001 for both comparisons). Subjects rated the clinician better in the areas of how much they liked being interviewed and how well they were able to describe their feelings. However, they were significantly more embarrassed with the clinician than with the IVR. Results support the psychometric properties of the IVR versions of the HAMD and HAMA scales. IVR technology presents new opportunities for expanding the utility of computerized clinical assessment.

Pharmacotherapy for obsessive-compulsive disorder.

BACKGROUND: Pharmacotherapy for obsessive-compulsive disorder (OCD) was seldom beneficial before clomipramine, a potent selective serotonin reuptake inhibitor (SSRI), became available. Subsequent progress in pharmacotherapy for OCD has increased the possibility of effective treatment for most sufferers. METHOD: Randomised controlled trials of pharmacotherapy for OCD were reviewed, as well as reports of beneficial pharmacotherapy found in open trials and case reports. RESULTS: SSRIs are well-tolerated by patients with OCD, even in large doses. Proserotonergic augmentation is seldom helpful but antipsychotic augmentations seem beneficial for many OCD patients with comorbid tics. CONCLUSIONS: Potent SSRIs are the pharmacotherapy of choice for OCD, with a more limited role reserved for monoamine oxidase inhibitors. If one SSRI is ineffective, others may be beneficial. Non-drug therapies are also important in OCD: behaviour therapy is frequently helpful but infrequently available and neurosurgery is sometimes helpful when all other treatments have failed.

Drug and diet interactions: avoiding therapeutic paralysis.

An explosion of information about drug and diet interactions has greatly complicated and confused the use of antidepressant drugs, yet if clearly understood, such information will actually enhance the safety and efficacy of these medications. The background against which antidepressants are discussed includes an overview of the cytochrome P450 (CYP) system (which now contains over 500 P450 genes), the concepts of enzyme specificity and selectivity, the roles of genetics and nonpharmacologic environmental factors, and examples of beneficial and detrimental drug and diet interactions. The comparative profiles of the various antidepressants are then presented with consideration given to their roles as substrates, inhibitors, and inducers of P450 enzymes such as CYP1A2, 2B6, 2C, 2D6, and 3A4. Examples of clinically important antidepressant drug/drug and drug/diet interactions are provided.

Computer-administered rating scales for social anxiety in a clinical drug trial.

Computer-administered versions of two clinician-administered symptom rating scales for social anxiety (the Liebowitz Social Anxiety Scale [LSAS] and the Brief Social Phobia Scale [BSPS]) and one paper-and-pencil scale (the Fear Questionnaire) were developed and utilized in a clinical trial for social phobia. The reliability and validity of the computer versions were examined, as were their equivalence to the traditional versions. Correlations between the computer and original versions were high at baseline, and remained high throughout the study. The internal consistency reliability of the computer scales was also high, and almost identical to the original versions. Mean score differences between computer and original versions were not significant at baseline, and no significant differences were found between computer and traditional versions on the amount of change detected from baseline to endpoint. Seventy-seven percent of subjects felt that the computer did not interfere with their visit at baseline and a plurality (36%) preferred the computer, with 30% preferring the clinician and 34% having no preference. By the end of the study, the plurality (41%) had no preference, with 27% preferring the computer and 32% preferring the clinician. Results support the use of these computer-administered symptom rating scales of social anxiety as a viable alternative to the clinician-administered versions with this subset of patients, which should offer researchers and clinicians a reliable and cost-effective method for evaluating social phobia.

Behavioral versus pharmacological treatments of obsessive compulsive disorder: a meta-analysis.

The goal of the study was to provide a quantitative analysis of the relative efficacy of all five currently available serotonin reuptake inhibitors (SRIs) and behavior therapy [exposure and response prevention (ERP)] for obsessive compulsive disorder. The relationship between effect size and methodological characteristics was also empirically examined. A search was conducted of several computerized databases covering the dates from 1973 to 1997. Seventy-seven studies were identified, yielding 106 treatment comparisons involving 4641 patients. Effect sizes were analyzed between individual interventions and between intervention class [SRI, ERP or the combined treatment of an SRI with ERP(ERP/SRI)]. Data were analyzed both before and after controlling for methodological variables. The effect size for clomipramine (CMI) was significantly greater than the other SRIs, with the exception of fluoxetine (FLX). CMI was not significantly greater than ERP or ERP/SRI. As a class, ERP was significantly greater than SRIs as a whole. Effect sizes were larger for studies without a control group or random assignment, for self-reported outcome measures, and varied significantly by method of effect size calculation. Year of publication was significantly related to effect size. When controlling for these methodological variables, CMI was not significantly greater than FLX or fluvoxamine (FLV), and ERP was no longer significantly greater than the SRIs as a whole. No significant difference was found between CMI and the other SRIs as a group in head to head trials. No differences in drop-out rates were found. CMI stands out from the other SRIs. This difference is probably not clinically significant enough to warrant first choice treatment, given CMI's greater lethality in overdose. The choice between an SRI or ERP is dominated primarily by the infrequent availability of ERP and to a lesser degree by personal preference. Methodological differences significantly impact effect size.

Drug interactions--friend or foe?

An explosion of knowledge about interactions of drugs with other drugs and with foods threatens to inundate clinicians. This review provides a better understanding of the cytochrome P450 system with a focus on those enzymes most involved in drug metabolism. Emphasis is placed on antidepressant medications, how they are metabolized by the P450 system, and how they alter the metabolism of other drugs. The role of antidepressants in precipitating the serotonin syndrome is also discussed.

Administration of the Hamilton Depression Rating Scale using interactive voice response technology.

We compared the reliability and equivalence of scores on the Hamilton rating scale for depression obtained by an interactive voice response (IVR) system and by human raters among 367 subjects 18 to 79 years old. Structured clinical interviews indicated that 93 of these subjects met the DSM-IV criteria for current major depression. We also examined short forms using the IVR data. The results obtained with the long (17-item) IVR interview correlated with those of the face-to-face interview, as did the results of the short (six- and eight-item) IVR interviews. In a random sample of 264 subjects, linear transformations of IVR results produced scores equivalent to clinical scores in the validation sample. We conclude that computerized assessment of the severity of depression by touch-tone telephone presents expanded opportunities for outcome research.