Benzodiazepines with fluoxetine

Non-motor signs of the disorder are also treatable with symptomatic medications. The frequent mood disorder can be treated with standard antidepressants, including tricyclics (such as amitryptiline) or serotonin reuptake inhibitors (SSRIs, such as fluoxetine or sertraline). This treatment is not without risks in these patients, as it may trigger manic episodes or may even precipitate suicide. Anxiety responds to benzodiazepines, as well as to effective treatment of depression. Long-acting benzodiazepines are favored over short-acting ones because of the lesser abuse potential. Some of the behavioral abnormalities may respond to treatment with the neuroleptics as well. The use of atypical neuroleptics, such as clozapine is preferred over the typical neuroleptics as they may help to control dyskinesias with relatively few extrapyramidal side-effects (Ch. 54). 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

Treatment of GAD can be undertaken using a number of pharmacological agents. Benzodiazepines have been found to be superior to placebo in several studies and all benzodiazepines appear to be equally effective. However, side effects include sedation, psvchomotor impairment, amnesia and tolerance (Chapter 1). Recent clinical data indicate that SSRIs and SNRIs are effective in the treatment of acute GAD symptoms. Venlafaxine, paroxetine and imipramine have been shown to be effective antianxiety medications in placebo-controlled studies. Case studies also indicate the usefulness of clomipramine, nefazodone, mirtazapine, fluoxetine and fluvoxamine in GAD. Buspirone, a 5-HTla receptor partial agonist, has been shown to be effective in several placebo-controlled, double-blind trials (Roy-Byme and Cowley, 2002). Buspirone has a later onset of action than both benzodiazepines and SSRIs but with the advantage of being non-addictive and non-sedating. 

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). 

Pharmacological treatments were used by nearly half of the 149 services which offered any treatment, with a wide range of medications directed at various features of cocaine usage. Fluoxetine and desipramine were the most frequently prescribed antidepressants, with benzodiazepines used to aid sleep and reduce distress in withdrawal states. Sedative antipsychotics were used, apparently in states of severe agitation as well as more directly for psychotic complications. 

A growing number of drugs are used that affect the many neurotransmitters in the brain benzodiazepines and others act on GABAergic transmission antidepressants, such as monoamine oxidase inhibitors and tricyclic antidepressants, are thought to increase the concentration of transmitter amines in the brain and so elevate mood—these will also act at peripheral nerve terminals, so interactions with them are a combination of peripheral and central actions. Levodopa (L-dopa) increases central as well as peripheral dopamine, and the newer class of psychoactive drugs, the selective serotonin reuptake inhibitors (SSRIs) of which the ubiquitous fluoxetine (Prozac) is best known, act in a similar way on serotonergic pathways. 

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). 

Corned answer = B. The anxiolytic properties of benzodiazepines, such as lorazepam, make them the drugs of choice in treating the anxiety and agitation of cocaine withdrawal. Lorazepam also has hypnotic properties. Phenobaibital has hypnotic properties but if s anxiolytic properties are inferior to those of the benzodiazepines. Cocaine itself could countered the agitation of withdrawal but its use would not be proper therapy. Hydroxyzine, an antihistaminic, is effective as an hypnotic and is sometimes used to deal with anxiety especially if emesis is a problem. Fluoxetine is an antidepressant with no immediate effects on anxiety. 

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). 

Recently, an association of kava and Parkinsonism has been noted. A 45-year-old healthy woman, absent any signs of Parkinson s disease but with a family history of essential tremor, was prescribed fluoxetine and benzodiazepines for depression. Approximately 3 months later, she developed severe Parkinson s disease after 10 days use of kava extract (32). 

Clinically important, potentially hazardous interactions with alprazolam, aprepitant, astemizole, atorvastatin, benzodiazepines, carbamazepine, chlordiazepoxide, cilostazol, clonazepam, clorazepate, colchicine, conivaptan, cyclosporine, dabigatran, dasatinib, diazepam, digoxin, dihydroergotamine, disopyramide, ergot alkaloids, fesoterodine, fluoxetine, flurazepam, fluvastatin, HMG-CoA reductase inhibitors, imatinib, ixabepilone, lapatinib, lopinavir, lorazepam, lovastatin, methylprednisolone, methysergide, midazolam, nilotinib, oxazepam, paroxetine, pimozide, pravastatin, prednisone, quazepam, repaglinide, rimonabant, rivaroxaban, sertraline, silodosin, simvastatin, solifenacin, temazepam, temsirolimus, tolvaptan, trabectedin, triazolam, warfarin, zidovudine... 

The SSRIs (paroxetine, fluoxetine, sertraline, fluvoxamine, citalopram) and SNRI (ven-lafaxine) have an impressive side-effect profile, and this has contributed to their widespread use. Possible adverse effects include nausea, insomnia, and agitation, but these are generally manageable and diminish over time. More significant is the association of the SSRIs with sexual dysfunction, in both men and women. These effects are longer lasting, and can occur in up to 40% of patients (79). A withdrawal syndrome has also been observed with the SSRIs, characterized by dizziness, headache, and irritability upon abrupt discontinuation. This is much less serious than that observed with benzodiazepines. 

Potentially clinically significant interactions include the tendency for fluvoxamine to increase circulating concentrations of oxidatively metabolized benzodiazepines, clozapine, theophylline, and warfarin. Sertraline and fluoxetine can increase levels of benzodiazepines, clozapine, and warfarin. Paroxetine increases levels of clozapine, theophylline, and warfarin. Fluoxetine also potentiates tricyclic antidepressants and some class 1C antiarrhythmics with a narrow therapeutic index (including encainide, flecainide, and propafenone). Nefazodone potentiates benzodiazepines other than lorazepam and oxazepam. 

Selective serotonin reuptake inhibitors (SSRIs) are the first-line therapy for PTSD. Efficacy for fluoxetine, paroxetine, and sertraline has been demonstrated in well-designed double-blind placebo-controlled studies to reduce all symptom domains (intrusive recollection, avoidance/numbness, and hyperarousal). - Other treatment options include the tricyclic antidepressants (TCAs) amitriptyline and imipramine and the irreversible monoamine oxidase inhibitor (MAOl) phenelzine, which have been shown to reduce re-experiencing. However, in comparison with SSRIs, TCAs and phenelzine are associated with a higher incidence of side-effects, risk of overdose, and poor compliance. Alprazolam has demonstrated anecdotal efficacy however, regular use of benzodiazepines is not recommended. Benzodiazepines can be used on an as-needed basis for specific symptoms (e.g. sleep disturbances). CBT has shown beneficial effects in relatively well-controlled studies, while the results with exposure therapy are... 

SSRI toxicity Fluoxetine and the other SSRls may cause nausea, headache, anxiety, agitation, insomnia, and sexual dysfunction. Jitteriness can be alleviated by starting with low doses or by adjunctive use of benzodiazepines. Extrap)Tamidal effects early in treatment... 

There is some evidence to suggest that the metabolism of some benzodiazepines (such as alprazolam, bromazepam, diazepam, and also possibly midazolam, nitrazepam and triazolam) may be reduced by some SSRIs (such as fluoxetine and fluvoxamine). On the whole, no clinically significant interaction appears to occur between other SSRIs and the benzodiazepines or related dri s such as cloral hydrate or zaleplon. There is some evidence to support the su estion that sedation is likely to be increased by the concurrent use of SSRIs and benzodiazepines. Rare cases of hallucinations have been seen with zolpidem and some SSRb. Symptoms of the serotonin syndrome have been reported in two patients taking paroxetine and a benzodiazepine. 

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