Proposing an algorithm for the pharmacological management of posttraumatic stress disorder.

The clinical management of posttraumatic stress disorder (PTSD) is as complex as the condition itself. Pharmacotherapy is an important component of this treatment process, which also includes psychosocial interventions and, in most cases, entails long-term efforts. The authors propose a systematic approach to the pharmacological treatment of PTSD using algorithmic techniques. After a careful history-taking phase and a review of available psychotropic agents, the practitioner usually ends up dealing with either PTSD alone or, more frequently, accompanied by other identifiable syndromes. Various antidepressants have demonstrated efficacy in the former, while the latter requires a management aimed at depressive, anxiety/dissociative, hypomanic/manic, or psychotic symptoms. The proposed algorithm provide guidelines for treatment issues such as medication choice, medication dose, maintenance pharmacotherapy, alternative options, and eventual outcomes. Algorithms summarize current information and suggest pharmacotherapy guidelines as a significant component of a comprehensive PTSD management program.

Comparison of recombinant cyclooxygenase-2 to native isoforms: aspirin labeling of the active site.

The search for isoform-specific enzyme inhibitors has been the focus of much recent research effort. Towards this goal, human recombinant cyclooxygenase-2 (EC 1.14.99.1, prostaglandin H synthase) was expressed in insect cells and purified to > 98% purity. Recombinant enzyme was characterized both by physical methods and activity measurements and shown to be fully active with kinetic properties similar to native COX-2 and COX-1. After detergent extraction, the enzyme had hydrodynamic properties indistinguishable from native bovine COX-1 and corresponded to the enzyme dimer as measured with size-exclusion chromatography. Peptide mapping via Lys-C protease identified a site of N-linked glycosylation and the aspirin covalent modification site. In the presence of heme, aspirin-specifically acetylated Ser-516. The enzyme will be suitable for biophysical studies and may lead to isoform-specific enzyme inhibitors.

Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating panic attacks: a meta-analysis.

The etiology and optimum treatment of panic disorder remain unclear. Imipramine and alprazolam are reasonably well established treatments. Several reports have suggested that serotonin reuptake inhibitors may also be effective for this condition. To investigate this issue, 27 published or presented placebo-controlled, double-blind studies of DSM-III or DSM-III-R panic disorder were subjected to meta-analysis. The serotonin reuptake inhibitors included paroxetine, fluvoxamine, zimelidine, and clomipramine. The standard treatments were imipramine or alprazolam. All three treatments were highly significantly superior to placebo in alleviating panic. The serotonin reuptake inhibitors were also significantly superior to both imipramine and alprazolam. The superiority of the serotonin reuptake inhibitors remained, but was less pronounced, when they were compared to the studies which used higher doses of imipramine or alprazolam. These findings underscore the importance of serotonin reuptake inhibitors in the treatment of panic disorder and indirectly add to the evidence that serotonergic abnormalities may have a role in its etiology.

A placebo-controlled double-blind multicenter trial of two doses of ipsapirone versus diazepam in generalized anxiety disorder.

Ipsapirone is a partial 5-HT1A agonist which appears promising for the pharmacologic treatment of anxiety. In this four-week, double-blind, 19-center study, 249 outpatients with generalized anxiety disorder were randomized to one of four treatments: ipsapirone, 5 or 10 mg t.i.d., diazepam 5 mg t.i.d., or placebo. Both active treatments were significantly superior to placebo in reducing anxiety symptoms, although response to ipsapirone was not significant until week 2 while diazepam had a more rapid onset. Five mg t.i.d. was the optimal ipsapirone dose. At 10 mg t.i.d. adverse experiences prompted more patients to discontinue treatment. Adverse experiences that were reported significantly more often for ipsapirone than placebo included asthenia, nausea, dizziness, paresthesias and sweating. Sedation was the most common diazepam-related side effect. The results of this study when combined with others suggest that 5 mg t.i.d. of ipsapirone is an effective and well-tolerated anxiolytic without many of the risks of benzodiazepine therapy. Dosage escalation by patients is unlikely because of an increased risk of side effects.

Potential indications for the selective serotonin reuptake inhibitors.

The selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, fluvoxamine, citalopram, paroxetine and sertraline. These medications may be effective for a variety of indications. The literature clearly supports their efficacy in some of these conditions in major depression. Data concerning their use in other areas is clearly preliminary but promising. These include reports of treatment of obsessive-compulsive disorder, atypical depression, panic disorder, premenstrual tension, eating disorders, substance use disorders, chronic pain, dementia, and personality disorders with aggressive or impulsive features. The variety of clinical uses for the SSRIs may compel re-examination of traditional diagnostic categories and theories of how antidepressants work.

An overview of paroxetine.

Paroxetine is a novel phenylpiperidine compound that acts as a selective serotonin reuptake inhibitor (SSRI). It is a more selective and potent SSRI than fluoxetine, sertraline, or fluvoxamine. Its pharmacokinetics are well suited to clinical use. Its half-life is approximately 24 hours, and it has no active metabolites. As with other SSRIs, there are few clinically significant drug interactions with paroxetine. Clinical studies consistently show that paroxetine alleviates moderate or severe depression and associated anxiety. It begins to act at least as rapidly as the tricyclic antidepressants. Animal data and limited human experience suggest relative safety in overdose and no evidence of teratogenicity. As with other SSRIs, the most common side effect of paroxetine is nausea, which is usually well tolerated. The nausea rarely leads to drug discontinuation or even dosage reduction. Little weight loss or weight gain occurs with paroxetine at doses used to treat depression, and the drug has no effect on the seizure threshold. Unlike other SSRIs, paroxetine has a relatively low incidence of anxiety and agitation. There is no evidence that paroxetine increases suicidal ideation. This supplement will contribute several important new papers to the literature on paroxetine.

Paroxetine in the treatment of depression: a comparison with imipramine and placebo.

Paroxetine is a selective serotonin reuptake inhibitor with significant antidepressant properties. This was a 6-week placebo- and imipramine-controlled study of 120 outpatients with major depression. Paroxetine was statistically significantly superior to placebo on almost all outcome measures. This was apparent as early as 1 week. Paroxetine was also significantly superior to imipramine on the Hamilton Rating Scale for Depression total score. Paroxetine was generally better tolerated than imipramine. These results strongly support paroxetine's effectiveness in the treatment of major depression and suggest that paroxetine will be a valuable addition to the options in treating depressive illness.

The safety profile of paroxetine.

Side effects remain one of the most important clinical issues in antidepressant therapy. Patients may not be able to take appropriate treatment or may not tolerate their medication in adequate doses or for an adequate length of time to manage their depressive illness. This article reviews the extensive safety data from 6705 patients treated with paroxetine. These data indicate that paroxetine has no significant cardiovascular effects, few significant drug interactions, and no clinically significant effects on the ECG or EEG. Furthermore, paroxetine is relatively safe in overdose and has very little anticholinergic activity. Psychomotor performance is not impaired by paroxetine and there is no evidence of any zimelidine-like hypersensitivity reactions or increase in suicidal ideation. As with other selective serotonin reuptake inhibitors (SSRIs), the most common side effect is gastrointestinal upset, especially nausea. This is usually very well tolerated and rarely leads to drug discontinuation. As with other SSRIs, monoamine oxidase inhibitors should not be prescribed concurrently or soon after discontinuing paroxetine because of the risk of a lethal interaction. Paroxetine may be less likely than currently available SSRIs to cause agitation. In general, paroxetine has a very favorable side effect profile and should be an important alternative in the medical treatment of depressive illness.

A controlled trial of adinazolam versus desipramine in geriatric depression.

Thirty outpatients between the ages of 60 and 85 with DSM-III Major Depression entered an 8 week randomized, double-blind comparison of desipramine and adinazolam mesylate, a triazolobenzodiazepine derivative. Outcome was assessed on several measures including the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Rating Scale, Clinical Global Impressions (CGI), the 35-item Self-Rating Symptom Scale, and Carroll Depression Scale. Patients in both groups demonstrated a highly significant decrease in average HDRS scores (p less than 0.001) over the course of the study. Adinazolam was associated with significantly greater reduction in average HDRS scores by the third day. Repeated measures analysis of variance showed a significantly greater reduction in HDRS scores for adinazolam over the course of the study. The study medications were associated with distinct patterns of adverse reactions. Desipramine more often produced dry mouth, constipation and nervousness, while adinazolam was more likely to cause drowsiness and lightheadedness. Three of these elderly patients, all of whom were taking desipramine reported at least one fall during the study. Adinazolam may be a promising agent in the treatment of depression in the elderly.

Adverse consequences of fluoxetine-MAOI combination therapy.

The authors describe two series of patients: 12 treated simultaneously with fluoxetine and a monoamine oxidase inhibitor and 6 patients started on treatment with an MAOI 10 days or more after stopping fluoxetine treatment. All patients had extremely refractory depression and were treated in open fashion before general knowledge was obtained of the side effects that may accompany the fluoxetine-MAOI combination. During the fluoxetine-MAOI trial, most patients continued to receive other psychotropic combinations that had been partially helpful. The use of fluoxetine and an MAOI, either together or in close succession, was accompanied by a very high incidence of adverse effects, especially the "serotonergic syndrome." This syndrome was characterized by mental status changes, such as hypomania and confusion, and physical symptoms, such as myoclonus, hypertension, tremor, and diarrhea. Because of the high incidence of side effects and the lack of definite efficacy, the concurrent use of fluoxetine and MAOIs should generally be avoided. The long half-lives of fluoxetine and norfluoxetine, as well as the prolonged metabolic effects of MAOIs, may also dispose patients to an interaction if one of the drugs is started soon after stopping the other.

A fixed-dose (300 mg) efficacy study of bupropion and placebo in depressed outpatients.

Two hundred twenty-four outpatients with major depression entered a 6-week, five-center, double-blind trial of bupropion 300 mg/day and placebo. A total of 216 patients were included in the efficacy analysis. In the combined center analysis, greater efficacy for bupropion was found on one or more measures (Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions) at treatment Days 21, 28, 35, and 42. Bupropion was well tolerated; only four adverse events were reported at least 5% more often in the bupropion group than in the placebo group. Six bupropion patients versus 5 placebo patients discontinued treatment because of adverse events. This study extends earlier findings of efficacy for higher-dose treatment in an inpatient population to lower-dose treatment in an outpatient population.

Conceptual tempo and resolution of social conflict by children.

Of 55 boys between 7 and 12 yr. old, 12 most reflective (on the Impulsivity score or conceptual tempo) chose an assertive alternative on the Social Reasoning Inventory more often than the 14 most impulsive boys. The observation replicates prior work but suggests conceptual tempo as a construct has unclear relevance to social reasoning.

A placebo-controlled inpatient comparison of fluvoxamine maleate and imipramine in major depression.

Fluvoxamine, a selective serotonin reuptake inhibitor, was investigated in a 6-week double-blind study among severely ill inpatients with DSM-III major depression. All but 1 patient also fulfilled criteria for melancholia. Following a 3-day placebo wash-out patients were randomly assigned to fluvoxamine, imipramine or placebo. Sixty of 81 patients completed at least 2 weeks following wash-out and were evaluated for efficacy. Analysis of covariance (controlling for baseline scores) showed significant (p less than 0.05) differences on CGI severity and BPRS total and a similar trend (p = 0.08) on the Hamilton Depression Scale. Fluvoxamine was superior (p less than or equal to 0.02) to both placebo and imipramine on these measures. Fluvoxamine's most common adverse effects were nausea and agitation. The number of fluvoxamine patients withdrawn for side-effects was less than imipramine and not significantly different than placebo. Fluvoxamine was not associated with significant changes in vital signs, ECG or laboratory tests. The results therefore indicate that fluvoxamine is a safe and highly effective treatment for hospitalized patients with major depression.

Avoidance training using an incremental vertical jump response in rats.

A procedure is described for conditioning a vertical jump avoidance response in rats. Employing an auditory signal and gradually increasing the height of the response platform, rats showed rapid acquisition of a jump response to avoid shock. While the average maximum height of the jump response increased between original training and retraining 7 days later, retraining 40 days later resulted in stable responding that was consistent with the first retraining session.

A double-blind comparison of fluoxetine, imipramine and placebo in outpatients with major depression.

Fluoxetine is the first selective serotonin reuptake inhibitor antidepressant to be marketed in the U.S. In this double-blind trial fluoxetine was compared with imipramine and placebo among 198 outpatients with DSM-III major depression, of whom 145 completed at least 2 weeks of active treatment and were evaluated for efficacy. Significantly fewer patients in each active drug group terminated early due to lack of efficacy compared to placebo. Both imipramine and fluoxetine were significantly superior to placebo on most measures. There were no consistently significant differences between the two active drugs although a trend favored imipramine on a number of measures. Fluoxetine was generally well tolerated. Significantly more imipramine than placebo patients terminated early due to side-effects while the fluoxetine-placebo difference was not significant. The results support previous studies which suggest fluoxetine's superior side-effect profile and the approximate antidepressant equivalence of fluoxetine and TCAs.

An overview of fluoxetine, a new serotonin-specific antidepressant.

Fluoxetine is a new, chemically unique antidepressant. In contrast with antidepressants already on the market, its only significant neurophysiologic effect is inhibition of serotonin reuptake. Double-blind comparisons show it is as effective in the treatment of major depression as tricyclic antidepressants. It is free of most of the troubling side effects of currently available antidepressants, including anticholinergic effects and weight gain. In fact, it is commonly associated with weight loss which is independent of nausea, the most commonly reported adverse effect. The recommended dose is 20 mg per day, given in the morning or early in the day. Fluoxetine deserves consideration for depressed patients for whom the clinician wishes to avoid anticholinergic effects, sedation, and weight gain. It may be especially effective in patients with pronounced obsessive-compulsive symptoms, weight gain with depression or from antidepressants, and in patients who have not responded to tricyclic therapy.

Paroxetine in the treatment of depression: a comparison with imipramine and placebo.

Paroxetine is a selective serotonin uptake inhibitor, which is being investigated as an antidepressant. In this double-blind, six-week study 120 outpatients with DSM-III major depression were randomly assigned to treatment with paroxetine, imipramine, or placebo. Results showed a statistically significant superiority of paroxetine over placebo on almost all outcome measures. Paroxetine was significantly superior to imipramine on the HAMD total score and was generally better tolerated than imipramine. The results support paroxetine's effectiveness in the treatment of major depression and suggest that further studies with this compound are warranted.

Serotonin-1A anxiolytics: an overview.

The selective serotonin-1A receptor partial agonist anxiolytics represent a new class of pharmacologic agents that have demonstrated efficacy in the treatment of generalized anxiety disorder (GAD). These compounds offer a completely different pharmacologic approach to this disorder from previous medications. The selective 5-hydroxytryptamine-1A (5-HT1A) anxiolytics buspirone, gepirone, ipsapirone, and SM-3997 have several important new and unique features that will be reviewed in this paper. These features include no cross-tolerance with alcohol or benzodiazepines, no evidence of abuse or misuse potential, and no withdrawal symptoms or rebound anxiety on cessation of therapy. The 5-HT1A anxiolytics have no muscle relaxant, sedative, or anticonvulsant properties and do not impair psychomotor functioning. They do have a slower onset of effect than standard benzodiazepines-clinical response is usually noted in 1-3 weeks. The side effect profile is quite different from that of the benzodiazepines. It includes gastrointestinal symptoms such as nausea and diarrhea, headache, dizziness, and restlessness. Some patients with GAD who have received chronic (greater than 1 month) benzodiazepine therapy may not respond as well to these compounds initially as will patients with no prior benzodiazepine treatment, especially if the benzodiazepine has been discontinued only recently. These compounds, buspirone in particular, have been shown to have excellent maintenance and prophylactic properties and to be well tolerated with long-term therapy (greater than 3 months). Because of their unique mechanism of action and side effect profile, and no evidence of misuse or abuse potential or interference with mental acuity, these compounds represent a definite advance in the pharmacologic management of GAD.