Alprazolam SSRIs

Panic disorder SSRIs Venlafaxine XR Alprazolam Clomipramine Clonazepam Imipramine Phenelzine... 

A metaanalysis showed that SSRIs, TCAs, and CBT are similarly effective. Alprazolam, clonazepam, sertraline, paroxetine, and venlafaxine are... 

Early controlled studies demonstrated the effectiveness of irreversible MAOIs, particularly phenelzine and tranylcypromine, for generalized social anxiety disorder. Prior to the advent of the SSRIs, MAOis were considered the gold standard treatment for social anxiety disorder. The best studied of the MAOis, phenelzine, has proved snperior to both beta blockers and the benzodiazepine alprazolam in treating generalized social anxiety disorder. 

The efficacy of beta-blockers in the symptomatic relief of anxiety in adults has been established in over a dozen controlled trials (Neppe, 1989). In a number of countries, beta-blockers have been licensed for the treatment of anxiety disorders. Somatic manifestations of anxiety such as palpitations, diaphoresis, and tremor, rather than core psychological symptoms, were particularly responsive to beta-blocker treatment. In comparative trials that included patients with severe anxiety and panic attacks, the antianxiety effect of beta-blockers was, however, somewhat less powerful than that of benzodiazepines (Lader, 1988), with the exception of a small trial that compared alprazolam to propranolol (Ravaris et ah, 1991). Head-to-head comparisons of beta-blockers and selective serotonin reuptake inhibitors (SSRIs) are lacking. Performance and stress-related anxiety that may affect public performers, such as musicians or people taking an examination or giving a speech, seems to be particularly suited for beta-blocker treatment (Lader, 1988). Beta-blockers may be given on an as-required basis 1-2 hours before the stressful situation. 

A larger set of placebo-controlled studies show conclusively that imipramine is also effective for the treatment of panic disorders. Other agents shown to be effective in panic disorders include the SSRIs paroxetine, sertraline, fluvoxamine, fluoxetine and citalopram. Generally, initial treatment of moderate to severe panic disorders may require the initiation of a short course of benzodiazepines e.g. clonazepam (0.5 1 mg twice daily), and an SSRI. The patient will obtain immediate relief from panic attacks with the benzodiazepine whereas the SSRI may take 1 6 weeks to become effective. Once a patient is relieved of initial panic attacks, clonazepam should be tapered and discontinued over several weeks and SSRI therapy continued thereafter. There are no pharmacological treatments available for specific phobias, however controlled trials have shown efficacy for several agents, e.g. phenelzine, moclobemide. clonazepam, alprazolam, fluvoxamine. sertraline and paroxetine in the treatment of social phobia (Roy-Byrne and Cowlev, 2002). 

Limited data exist to support drug management in phobic disorders. Behavioral techniques, especially for specific phobic conditions, are currently the treatment of choice. MAOIs, SSRIs, clonidine, and alprazolam may benefit some patients. Figure 12-3 summarizes the management strategy we would recommend. 

Results from studies comparing TCAs, SSRIs, and MAOIs with placebo in the treatment of PD are summarized in Table 13-5, Table 13-6, and Table 13-7. The results of studies comparing alprazolam or SSRIs with standard TCAs are summarized in Table 13-8 and Table 13-9. All drugs were superior to placebo, although no significant differences in efficacy were noted among them. 

SSRIs sometimes cause an initial jitteriness similar to that noted with initial imipramine therapy for PD. This may be more common with SSRIs than with other currently available non-TCA antidepressant therapies for PD. Just as low initial imipramine doses avert this reaction, initiating SSRI therapies with one fourth to one half the usual starting antidepressant dose followed by gradual increments with low doses can avert this reaction. This syndrome can also be blocked by add-on, low-dose, as-needed BZD therapy (e.g., alprazolam or lorazepam). 

A third important CYP450 enzyme for antidepressants and mood stabilizers is 3A4. Some benzodiazepines (e.g., alprazolam and triazolam) are substrates for 3A4 (Fig. 6—17). Some antidepressants are 3A4 inhibitors, including the SSRIs fluoxetine and fluvoxamine and the antidepressant nefazodone (Fig. 6—18). Administration of a 3A4 substrate with a 3A4 inhibitor will raise the level of the substrate. For example, fluoxetine, fluvoxamine, or nefazodone will raise the levels of alprazolam or triazolam, requiring dose reduction of the benzodiazepine (Fig. 6—18). 

Insomnia is a common comorbid condition with depression, and frequently is made worse by antidepressants, particularly the SSRIs. When insomnia persists despite adequate evaluation and attempts to reduce it by other approaches, it is often necessary to use a concomitant sedative-hypnotic, especially a short-acting nonbenzodiazepine with rapid onset such as zaleplon or zolpidem. At times a benzodiazepine sedative hypnotic such as triazolam or temazepam may be necessary. If anxiety persists during the day and cannot be otherwise managed, it may be necessary to add an anxiolytic benzodiazepine such as alprazolam or clonazepam. Use of sedative-hypnotics and anxiolytics should be short-term whenever possible. 

Drug combinations Probably the most common combination treatment is concomitant use of an SSRI and a benzodiazepine, especially on initiation of treatment (Fig. 9—6). The benzodiazepines (especially alprazolam and clonazepam) not only appear to act synergistically to increase the onset of therapeutic action and perhaps even boost the efficacy of SSRIs, but they also appear to block the anxiogenic actions of the SSRIs and lead to better tolerability as well as the ability to attain therapeutic dosing levels for the SSRIs. Sometimes sedative-hypnotics such as zale-plon or zolpidem are required in addition to an SSRI, especially on initiation of SSRI treatment. 

Switching - alternative SSRI a second-generation antidepressant a high potency benzodiazepine such as alprazolam. 

SSRIs and the benzodiazepine alprazolam are often used to treat panic disorder. Pharmacokinetic reactions between them could therefore be important. Alprazolam is metabolized by CYP3A4, which fluvoxamine inhibits (SEDA-22, 13). In 23 out-patients (11 men, 12 women, mean age 39 years) who took alprazolam both as monotherapy (mean dose 1.0 mg/day) and in combination with fluvoxamine (mean dose 34 mg/day), fluvoxamine increased plasma alprazolam concentrations by 58% (97). This was not associated with increased sleepiness, measured by a subjective rating scale, but objective measures of psychomotor function were not carried out and these could have been impaired by raised alprazolam concentrations. 

The effects of SSRIs on alprazolam pharmacokinetics have been studied in 21 healthy volunteers (age and sex not given) who were pre-treated with either fluoxetine or citalopram (20 mg/day for 21 days) (98). Fluoxetine increased the AUC of a single 1.0 mg dose of alprazolam by 32% citalopram had no effect. These findings are consistent with previous reports that fluoxetine and its active metabolite, norfluoxetine, produce moderate inhibition of CYP3A4 while citalopram does not. 

A within-subject, double-bhnd, placebo-controlled, parallel design has been used to measure the effects of citalo-pram (20 mg/day) and fluoxetine (20 mg/day) on the pharmacokinetics and pharmacodynamics of alprazolam (1 mg/day) (45). Fluoxetine significantly impaired the metabolism of a single oral dose of alprazolam 1 mg, leading to prolongation of the half-life and an increased AUC, whereas citalopram did not. Neither SSRI significantly affected the pharmacodynamic effects of alprazolam. This experiment suggests differential effects of citalopram and fluoxetine on alprazolam kinetics. 

FLUOXETINE, FLUVOXAMINE, PAROXETINE BZDs - ALPRAZOLAM, DIAZEPAM, MIDAZOLAM t in plasma concentrations of these BZDs. Likely t sedation and interference with psychomotor activity Alprazolam, diazepam and midazolam are subject to metabolism by CYP3A4. Fluvoxamine, fluoxetine and possibly paroxetine are inhibitors of CYP3A4 sertraline is a weak inhibitor. SSRIs are relatively weak compared with ketoconazole, which is possibly 100 times more potent as an inhibitor Warn patients about risks associated with activities that require alertness. Consider use of alternatives such as oxazepam, lorazepam and temazepam, which are metabolized by glucuronidation >- For signs and symptoms of CNS depression, see Clinical Features of Some Adverse Drug Interactions, Central nervous system depression... 

Treatment. The choice lies between a fast-acting benzodiazepine such as alprazolam (1-3 mg/day p.o.) and a drug with delayed efficacy but fewer problems of withdrawal such as a TCA, e.g. clomipramine (100-250 mg/day p.o.) or an SSRI, e.g. paroxetine (20-50 mg/day p.o.). The different time course of these two classes of agent in panic disorder is depicted in Fig. 19.5 (see also Tables 19.5 and 19.6). 

Some SSRIs (notably fluvoxamine and to a lesser extent fluoxetine) and their metabohtes inhibit hepatic oxidative enzymes, particularly CYP2C19 and CYP3A, that metabolize most benzodiazepines, as well as zaleplon, zolpidem, zopiclone, and buspirone (SEDA-22, 39) (SEDA-22, 41) (168,169). Apart from fluvoxamine, SSRIs do not generally have a chnically prominent effect on hypnosedative effects studies vary from those that have found that fluoxetine has a moderate but functionally unimportant impact on diazepam concentrations (170) to results that suggest significant aggravation of the cognitive effects of alprazolam when co-prescribed with the SSRI (171). 

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