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BACKGROUND: There is a warning associated with all serotonergic antidepressants and its concomitant use with tramadol due to the concern for a drug-drug interaction resulting in serotonin syndrome (SS). The prescribing of antidepressants with tramadol may be unnecessarily restricted due to fear of causing this syndrome. OBJECTIVES: There are 3 objectives of this review. To (1) review case reports of SS associated with the combination of tramadol and antidepressant drugs in recommended doses, (2) describe the mechanisms of the drug interaction, and (3) identify the potential risk factors for SS. METHODS: Case reports of SS associated with tramadol and antidepressants were identified via Cochrane Library, PubMed, and Ovid (through October 2012) using search terms SS, tramadol, antidepressants, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, milnacipran, trazodone, vilazodone, and bupropion. Cases involving monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were excluded. RESULTS: Nine articles were identified describing 10 cases of suspected SS associated with therapeutic doses of tramadol combined with an antidepressant. Mechanisms of the drug-drug interactions involve pharmacodynamic, pharmacokinetic, and possible pharmacogenetic factors. CONCLUSIONS: Review of the available case reports of tramadol combined with antidepressant drugs in therapeutic doses indicates caution in regard to the potential for SS but does not constitute a contraindication to their use. Tramadol is only contraindicated in combination with MAOIs but not other antidepressants in common use today. These case reports do suggest several factors associated with a greater risk of SS, including increased age, higher dosages, and use of concomitant potent cytochrome P450 2D6 inhibitors. Tramadol can be safely combined with antidepressants; however, monitoring and counseling patients are prudent when starting a new serotonergic agent or when doses are increased.

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In recent years, the frequency of antidepressant drug-induced sexual dysfunction has increased, along with the use of new drugs for the treatment of erectile dysfunction and premature ejaculation. It has thus become common for pharmacists to counsel patients about sexual issues. Pharmacists must not only become knowledgeable about these drugs and their indications, but they must also become skilled and comfortable with counseling patients and answering questions from both patients and other health care providers. In addition to therapeutic information, pharmacists' discussions with patients should take into account factors that contribute to treatment nonadherence and treatment failure. Patient education is essential to ensure optimum outcomes for pharmacologic treatments for both erectile dysfunction and premature ejaculation. Improper use of phosphodiesterase-5 inhibitor drugs for erectile dysfunction accounts for most nonresponsiveness and discontinuation of treatment. Drug-induced sexual dysfunction is common with some psychotropic drugs. Up to 50% of men will experience delayed ejaculation, and at least 30% of men and women will experience anorgasmia from antidepressant drugs with serotonin agonist activity. Trazodone is the drug most commonly associated with the rare but very serious adverse effect of priapism. The pharmacist who is both competent and comfortable discussing sexual function and dysfunction with patients can make positive contributions to their therapeutic outcomes as well as their quality of life.

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Psychotropic drugs are often associated with sexual dysfunction. The frequency of antidepressant-associated sexual dysfunction is greatly underestimated in clinical trials that rely on patient self-report of these adverse events. Direct inquiry reveals that delayed orgasm/ejaculation occurs in >50% and anorgasmia in at least one third of patients given selective serotonin reuptake inhibitors. Antidepressant-induced sexual dysfunction can be successfully managed. A different antidepressant without significant sexual effects, such as bupropion or mirtazapine, can often be substituted. Other strategies involve drug holidays or adjunctive therapy with drugs such as sildenafil. Dopamine antagonist antipsychotic drugs are most commonly associated with decreased libido. The newer atypical antipsychotics, with less effect on dopamine, are less commonly associated with sexual dysfunction. Sexual dysfunction is commonly reported with seizure disorders, and many anticonvulsant drugs affect levels of sex hormones. Because sexual dysfunction can be related to many factors, care must be taken to establish the patient's baseline sexual functioning before the initiation of psychotropic drug therapy and to rule out other etiologies before drugs are implicated as causative.

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Sexual dysfunction is a frequently encountered comorbid condition in patients with many medical and psychiatric conditions, such as epilepsy and depression. Most depressed patients experience some type of sexual dysfunction, decreased sexual desire being the most common. The association of sexual dysfunction with epilepsy is less clear. Changes in sex hormone levels are common in patients with epilepsy and may be attributable to the disease or to antiepileptic drugs (AEDs). Sexual dysfunction associated with depression or epilepsy is generally treated according to standard guidelines for the management of sexual disorders, since data from special populations are not available. The most common forms of female sexual dysfunction are lack of sexual desire and difficulty achieving orgasm. There are no approved pharmacotherapies for female hypoactive sexual desire disorder or female orgasmic disorder. Female sexual arousal disorder is treated with estrogen replacement therapy when indicated or vaginal lubricants. The most common male sexual dysfunction disorders are premature ejaculation and erectile dysfunction. Phosphodiesterase type-5 inhibitor drugs are now the first-line treatment for erectile dysfunction, and selective serotonin reuptake inhibitors and topical anesthetic creams are nonapproved but effective treatments for premature ejaculation. Testosterone and aromatase inhibitors have been used investigationally to treat sexual dysfunction in men taking AEDs. Patient education and follow-up appointments are essential to ensure optimal outcomes of pharmacologic treatments for sexual dysfunction.

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BACKGROUND: A long-acting, injectable risperidone formulation is the first depot atypical antipsychotic drug to become available in the United States. OBJECTIVE: The intent of this article is to review the efficacy and safety data available for long-acting, injectable risperidone. METHODS: Information was identified via MEDLINE (years, 1990-May 2004) using the terms risperidone, long-acting injectable, depot, and delayed-action preparations. The manufacturer also provided information about risperidone in the form of abstracts and summaries of professional meetings. RESULTS: Several 12-week studies and one 12-month study suggest that long-acting risperidone is an effective and well-tolerated treatment option for the maintenance therapy of schizophrenia. Thus far, no unexpected adverse events have been reported with the long-acting formulation. Extrapyramidal symptoms with long-acting risperidone were uncommon, dose-related, and similar to those observed with oral risperidone in short-term trials. A small, dose related weight gain occurred with long acting risperidone, again similar to that seen with oral risperidone. Pain at the injection site was uncommon and decreased with continued administration. The long-acting, injectable formulation comes in an aqueous suspension of microspheres. There is no initial drug release after injection; the main release of risperidone begins at week 2 to 3 postinjection, increases during weeks 3 and 4, is maintained during weeks 4 through 6, and declines between weeks 6 and 7. With repeated injections every 2 weeks, steady-state levels are usually reached by weeks 6 to 8. For most patients, the initial dosage should be 25 mg every 2 weeks, and oral administration should continue for the first 3 weeks after initial injection. Doses can be increased every 8 weeks to a maximum of 50 mg every 2 weeks. CONCLUSION: Long-acting risperidone offers clinicians a combination of the benefits of a depot antipsychotic drug with the therapeutic advantages of an atypical antipsychotic drug.

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BACKGROUND: venlafaxine has been available for use as an antidepressant in the United States for a decade. OBJECTIVE: Comprehensive reviews of venlafaxine have been published elsewhere; thus, this update focuses on newer issues of treatment remission in depression, treatment-resistant depression, and extended-release venlafaxine for generalized anxiety disorder (GAD). METHODS: Relevant clinical literature from 1993 through 2003 was identified from database searches of MEDLINE and International Pharmaceutical Abstracts, and from manual searches of reference lists of the identified papers. Search terms included venlafaxine extended-release, venlafaxine XR, treatment-resistant depression, depressive disorders, anxiety disorders, generalized anxiety disorder, and antidepressive agents second generation. RESULTS: With its dual action of serotonin and noradrenergic reuptake inhibition, venlafaxine has been shown to be superior in efficacy to selective serotonin reuptake inhibitors for severe major depressive disorder, treatment-resistant depression, and depressive symptom remission. Its demonstrated efficacy for both short- and long-term treatment of GAD has led to its use for obsessive-compulsive disorder and chronic pain syndromes, although inadequate clinical literature currently exists to support these latter 2 uses. In the past decade, no new or unexpected adverse events have been identified with venlafaxine therapy, except a possibly greater risk of fatal overdose compared with other serotonergic drugs, suggesting the need for caution in patients with suicidal ideation. Because venlafaxine is a potent serotonin agonist, caution must also be exercised to prevent the possibility of serotonin syndrome when used with other serotonin agonists, and its dose should be tapered very gradually to minimize the risk of a serotonin withdrawal reaction. CONCLUSION: Venlafaxine has emerged as a successful post-SSRI-era antidepressant with an expanded range of uses since it was first marketed.

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In May 1996, the California Medicaid Program (Medi-Cal) added two SSRI antidepressants to its formulary to facilitate the substitution of the SSRIs for older medications as clinically warranted, especially in minority patients thought to be particularly at risk for poor outcomes using older medications. Moreover, it was expected that the overall use of antidepressants would increase as patients who experienced sub-optimal outcomes prior to the formulary expansion would again seek treatment once new options were available. The formulary expansion did significantly alter the clinical treatment decision process, resulting in an immediate and sustained increase in the number of depressed patients initiating antidepressant therapy, primarily with the added SSRIs. This increase in SSRI use after the formulary expansion cannot be fully attributed to desired substitution effects, such as the narrowing of racial differences in SSRI use. However, while some expansion in overall antidepressant use may have been desired, the clinical validity of this expansion cannot be determined based on the results presented here.

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BACKGROUND: The California Medicaid (Medi-Cal) program removed prior authorization restrictions for 2 selective serotonin reuptake inhibitors (SSRIs), fluoxetine and paroxetine, in May 1996. OBJECTIVE: This article documents how open access affected patient compliance and the likelihood of switching antidepressant therapies. METHODS: All Medi-Cal patients with a paid claim who had a diagnosis of major depressive disorder (MDD) from September 1994 through January 1999 were eligible. The impact of open access on patient compliance and drug switching was investigated using logistic regression models. Completed therapy was defined as 180 days of uninterrupted drug therapy at a minimum therapeutic dose. RESULTS: A total of 6409 patient treatment episodes were identified, of which 80% involved the use of an antidepressant. The aggregate rate of drug therapy completion dropped from 23.2% before the change in formulary policy to 20.5% in the open-access period. There was no corresponding change in the likelihood of switching therapies. For fluoxetine-treated patients, the odds ratio for completing therapy relative to tricyclic antidepressant-treated patients dropped from 3.916 to 1.706 in the open-access period. Corresponding results for paroxetine-treated patients were 1.591 and 0.726, respectively. The reduction in the likelihood of completed therapy without a corresponding increase in switching is consistent with earlier results. Open access resulted in an influx of patients who were not previously treated with an antidepressant or reported by their physician as having an MDD. Physicians may have expanded the use of the open-access SSRIs to treat less severely ill patients. However, paid claims data do not provide sufficient information to accurately measure severity of illness. CONCLUSIONS: It is unclear whether patients benefited clinically from the expansion of the Medi-Cal formulary. The significant changes in the characteristics of the patient population in response to open access (access effect) complicate attempts to measure the impact of open access on treatment patterns. Future analysis of the impact of open access on the cost of treating an episode of depression will also have to address this issue.

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BACKGROUND: Bipolar disorder affects approximately 1% of the population at an annual cost of $45 billion in the US. Estimates of non-compliance with mood stabilizer therapy range as high as 64%. The objective of this study was to document the use patterns with mood stabilizers achieved by patients with bipolar disorder and to estimate the direct health care costs associated with sub-optimal drug therapy. METHODS: Paid claims for 3,349 California Medicaid patients with bipolar disorder were used to document the use patterns for mood stabilizers achieved by patients with bipolar disorder. The impact of the patient's drug use patterns on likelihood of antipsychotic or antidepressant use within 1 year and health care costs incurred during the first posttreatment year were also estimated. RESULTS: Only 42.4% of patients used a mood stabilizer during the first posttreatment year; over 60% of treated patients switch or augment their initial therapy within 1 year, and only 5.5% of patients used a mood stabilizer consistently for 1 year. Direct health care costs were significantly higher among those patients who delayed or did not use mood-stabilizing agents during the first year. LIMITATIONS: Medi-Cal covers poor and disabled patients and is not representative of the general population. Paid claims data do not include clinical markers for severity of illness or treatment response. CONCLUSIONS: Suboptimal use patterns for mood stabilizing medications were frequent and costly. Strategies to improve compliance with mood stabilizer regimens, along with new treatment options, are needed to improve treatment outcomes.

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BACKGROUND: Over the past decade, use of the atypical antipsychotic drugs clozapine, risperidone, olanzapine, and quetiapine has significantly changed the treatment of schizophrenia in the United States. The ability to make optimal drug choices will depend on determining whether there are clinically important differences between these drugs. OBJECTIVE: This review describes ziprasidone, the most recently introduced antipsychotic drug. Its mechanism of action, pharmacokinetics, and adverse-effect profile are discussed, and the results of clinical efficacy trials are summarized. METHODS: This review of ziprasidone is based on data from premarketing clinical efficacy and safety trials, a briefing document from the US Food and Drug Administration Psychopharmacological Drugs Advisory Committee, published studies, and abstracts presented at national and international meetings. International Pharmaceutical Abstracts and MEDLINE were searched for relevant citations, with no limitation on year. RESULTS: Ziprasidone has been reported to be an effective antipsychotic drug for both positive and negative symptoms of schizophrenia, and long-term use has been effective in preventing relapse. Its 5-hydroxytryptamine (HT)1D-antagonist and 5-HT(1A)-agonist activity are consistent with a potential for antidepressant and anxiolytic activity beyond its antipsychotic effects. Ziprasidone has been associated with a low incidence of sedative effects, a low likelihood of extrapyramidal symptoms and postural hypotension, and no anticholinergic effect, although it may cause transient hyperprolactinemia. Unlike most atypical antipsychotic drugs, ziprasidone is not associated with weight gain, hyperlipidemia, or elevated plasma glucose levels. It is, however, more likely than other atypical antipsychotic drugs to increase the QTc interval (QT interval corrected for heart rate). For acute psychotic symptoms in patients with schizophrenia, schizoaffective disorder, or acute mania, ziprasidone is administered twice daily at a usual daily dose of 80 to 160 mg, whereas 40 mg/d may be an effective maintenance dose. CONCLUSIONS: Differences in efficacy and tolerability between existing atypical antipsychotic drugs allow individualization of drug therapy for patients with schizophrenia or schizoaffective disorder. Ziprasidone differs from other atypical antipsychotic drugs in several clinically important ways, although further experience is necessary to clarify the significance of these differences.

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