Glen L. Stimmel

Mirtazapine: An Antidepressant with Noradrenergic and Specific Serotonergic Effects

Mirtazapine is a unique antidepressant that refines the specificity of effects on noradrenergic and serotonergic systems. It is an antagonist of presynaptic α2‐adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin (5‐HT) presynaptic axons, plus is a potent antagonist of postsynaptic 5‐HT2 and 5‐HT3 receptors. The net outcome of these effects is increased noradrenergic activity together with specific increased serotonergic activity, especially at 5‐HT1A receptors. This mechanism of action maintains equivalent antidepressant efficacy but minimizes many of the adverse effects common to both tricyclic antidepressants and selective serotonin reuptake inhibitors. Mirtazapine has an onset of clinical effect in 2–4 weeks similar to other antidepressants, although sleep disturbances and anxiety symptoms may improve in the first week of treatment. It has minimal cardiovascular and anticholinergic effects, and essentially lacks serotonergic effects such as gastrointestinal symptoms, insomnia, and sexual dysfunction. Sedation, increased appetite, and weight gain are more common with mirtazapine than with placebo. An elimination half‐life of 20–40 hours enables once‐daily bedtime dosing. The recommended initial dosage is 15 mg once/day at bedtime, with an effective daily dosage range of 15–45 mg. Cases of overdose of up to 975 mg caused significant sedation but no cardiovascular or respiratory effects or seizures.

Venlafaxine: a 2003 update.

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.

Ziprasidone: An atypical antipsychotic drug for the treatment of schizophrenia

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.

Cost of treating bipolar disorder in the California Medicaid (Medi-Cal) program

BACKGROUND Bipolar disorder affects approximately 1% of the population at an annual cost of

Antidepressants and the risk of seizures.

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 patients 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.

Sexual dysfunction and psychotropic medications.

As new antidepressants have been marketed, the issue of drug‐induced seizures has assumed new relevance. The risk of such seizures depends on at least three critical factors. Of most importance are an individuals predisposing factors that may increase the risk, followed by the amount and rate of dosage titration, and the relative epileptogenic potential of the particular drug.

A retrospective analysis of the revocation of prior authorization restrictions and the use of antidepressant medications for treating major depressive disorder

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 patients baseline sexual functioning before the initiation of psychotropic drug therapy and to rule out other etiologies before drugs are implicated as causative.

Benzodiazepines in schizophrenia.

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.

Serotonin Syndrome Is It a Reason to Avoid the Use of Tramadol With Antidepressants

Benzodiazepines have a checkered history in the United States; public and professional attitudes about them have ranged from their being wonder drugs in the 1970s to being virtually purged from many formularies as addictive and dangerous in the 1980s. The attitude today is that they are useful for specific indications. In the last 20 years they have been investigated as adjunctive agents to conventional antipsychotic drugs in the treatment of schizophrenia. Benzodiazepines may be effective in schizophrenia because stress is one mediator of relapse in these patients. In addition, inhibition of dopamine neurotransmission through γ‐aminobutyric acid‐enhancing activity may provide a direct antipsychotic effect. As monotherapy or adjuncts to antipsychotic agents, benzodiazepines produced antipsychotic effects in schizophrenia in approximately 50% of controlled trials. Although there is no particular benzodiazepine of choice, low‐potency compounds with long elimination half‐lives are recommended. Adverse effects of concern include sedation and cognitive impairment, behavioral disinhibition, exacerbation of psychotic symptoms, and the potential for dependence, withdrawal, and abuse. The recent arrival of atypical antipsychotic drugs has significantly slowed research and interest in benzodiazepines in schizophrenia beyond their initial beneficial sedative effects for acute psychotic episodes.

Management of and Counseling for Psychotropic Drug‐Induced Sexual Dysfunction

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.