Paroxetine dosing

Paroxetine. Wheadon and associates [1993] reported the results of a 12-week, fixed-dose, multicenter study of 348 patients with OCD. The subjects were randomly selected in a double-blind fashion to receive either 20 mg, 40 mg, or 60 mg of paroxetine or placebo. Statistical analysis revealed improvement for the two higher paroxetine doses as compared with that of placebo. In a further analysis of the results, M. Steiner et al. (1994) reported that male gender, lack of comorbidity, and longer illness correlated with greater improvement with the paroxetine treatment. Patients with moderate OCD responded to 40 mg of paroxetine, whereas patients with severe OCD (Y-BOCS > 26] showed a greater response with the 60-mg dose. 

For patients with severe problems discontinuing paroxetine, dosing may need to be tapered over many months (i.e., reduce dose by 1 % every 3 days by crushing tablet and suspending or... 

Differences exist in primary care between the patterns of prescribing fluoxetine, paroxetine or sertraline, which may influence cost outcomes. Sertraline-treated patients are more likely to have their dose increased (Sclar et al, 1995 Donoghue, 1998), and to drop out of treatment prematurely (Donoghue, 1998). The apparent need to titrate doses upwards with sertraline may require more involvement by the clinician and may delay response to treatment, with resultant increases in direct health costs (Sclar et al, 1995). However, these economic findings are retrospective, may suffer from selection bias, and being derived from HMO patients may not be generalizable to other populations confirmation in further studies is required. 

In initial ICC studies, animals were treated with MDA or MDMA using the protocol described by Ricaurte et al. (1985). Adult Sprague-Dawley rats (150 to 200 g) reeeived subcutaneous injections of racemic MDA or MDMA every 12 hours for 4 days. Each dose was equivalent to 20 mg/kg of the free base. The rats were sacrificed by intracardiac aldehyde perfusion 2 weeks after the final dose. In order to study subacute effects for evidence of degeneration, additional rats received MDA every 12 hours for 2 days and were sacrificed 24 hours after the last injection. Additional experimental details are described elsewhere (O Heam et al. 1986 O Heam et al. 1988). A series of animals treated identically and in parallel were analyzed for changes in 5-HT levels and density of uptake sites using paroxetine binding (Yeh et al. 1986 Battaglia et al. 1987). 

Venlafaxine extended release, in doses of 75 to 225 mg/day, improves social anxiety, performance, and avoidance behavior with a reduction in disability.61 Treatment with venlafaxine results in response rates similar to those seen with paroxetine.60 Venlafaxine may be effective in SSRI non-responders.62 As with SSRIs, doses should be tapered slowly when discontinuing therapy. Tolerability is similar to that observed in depression trials with venlafaxine extended release. Common side effects are anorexia, dry mouth, nausea, insomnia, and sexual dysfunction. 

SSRIs Citalopram 10-30 mg fluoxetine 10-20 mg fluvoxamine 50 mg paroxetine 10-30 sertraline 25-150 mg all agents are given by mouth daily and can be dosed continuously or during the luteal phase only26 Sexual dysfunction (reduced libido, anorgasmia), insomnia sedation, hypersomnia, nausea, diarrhea... 

SSRIs are theorized to reduce the frequency of hot flashes by increasing serotonin in the central nervous system and by decreasing LH. Of the SSRIs, citalopram, paroxetine, and sertraline all have been studied and have demonstrated a reduction in hot flashes while treating other symptomatic complaints such as depression and anxiety.33 Venlafaxine, which blocks the reuptake of serotonin and norepinephrine, has demonstrated a reduction in hot flashes primarily in the oncology population.34 Overall, these antidepressant medications offer a reasonable option for women who are unwilling or cannot take hormonal therapies, particularly those who suffer from depression or anxiety. These agents should be prescribed at the lowest effective dose to treat symptoms and may be titrated based on individual response. 

Risperidone Aripiprazole 2D6 > 3A4 2D6, 3A4 Carbamazepine and phenytoin topiramate hypericum (St. John s Wort). Paroxetine, fluoxetine, sertraline (high dose) grapefruit juice 2D6 or 3A4 substrates acting as competitive inhibitors. 

The pharmacokinetics of hyperforin have been studied in rats and humans (Biber et ai. 1998). In rats, after a 300 mg/kg orai dose of hypericum extract (WS 5572, containing 5% hyperforin), maximum piasma ieveis of 370 ng/mi (690 nM) are achieved at 3 hours. The haif-iife of hyperforin is 6 hours. Humans given a 300 mg tabiet of hypericum (containing 14.8 mg hyperforin) showed maximum piasma ieveis of 150 ng/mi (280 nM) at 3.5 hours. The haif-iife is 9 hours, and mean residence time is 12 hours. Pharmacokinetics of hyperforin are iinear up to 600 mg, and no accumuiation occurs after repeated doses. By comparison, effective and safe piasma ieveis of paroxetine and fluoxetine vary between 40 and 200 ng/mi (Preskorn 1997). The effective piasma concentration of hyperforin predicted from computer-fit data is approximateiy 97 ng/mi (180 nM), which couid be easiiy monitored (Biber et ai. 1998). There is a iinear correiation between orai dose of hyperforin and piasma ieveis, and steady-state concentrations of 100 ng/mi (180 nM) couid be achieved with three-times-daiiy dosing. 

KUlen JD, Fortmann SP, Davis L, Strausberg L, Varady A (1999) Do heavy smokers benefit from higher dose nicotine patch therapy Exp Clin Psychopharm 7 226-233 KUlen JD, Fortmann SP, Schatzberg AF, Hayward C, Sussman L, Rothman M, Strausberg L, Varady A (2000) Nicotine patch and paroxetine for smoking cessation. J Consult Clin Psych 68 883-889... 

SSRls. SSRI antidepressants have also received considerable scrutiny in the treatment of OCD. Fluoxetine, fluvoxamine, paroxetine, and sertraline are all approved by the FDA for the treatment of OCD. Current studies suggest that each of these medications is more effective for OCD when administered at the higher end of the therapeutic dose range, that is, fluoxetine 60-80 mg/day, fluvoxamine 200-300 mg/ day, paroxetine 40-60 mg/day, and sertraline 150-200 mg/day. No controlled studies are yet available regarding the use of citalopram or escitalopram for OCD. Refer to Chapter 3 for more information regarding SSRl antidepressants. 

Serotonin-Boosting Antidepressants. The SSRIs have also been studied in the treatment of generalized social anxiety disorder, and paroxetine, sertraline, and venlafaxine are effective. Preliminary data suggests that the serotonin-boosting atypical antidepressants (mirtazapine and nefazodone) may also be helpful. Like the MAOIs, they appear to be effective at doses comparable to those used to treat depression. They may help avoidant patients to gradually increase their social interaction and become more assertive. 

Medications that enhance norepinephrine activity can do so in one of several ways. First, they can block the reuptake of norepinephrine back into the nerve cell once it has been released. This keeps the norepinephrine in the synapse longer and therefore makes it more active. The tricyclic antidepressants (TCAs), duloxetine (Cymbalta), and venlafaxine (Effexor) act in this manner, as does paroxetine (Paxil) at higher doses. Atomoxetine (Strattera), a treatment for ADHD, also works in this way. 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

Elderly Clearance of fluvoxamine is decreased by about 50% in elderly patients. A lower starting dose of paroxetine is recommended. Sertraline plasma clearance may be lower. In 2 pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared with younger subjects, and its half-life was increased by 30% and 50%, respectively. In 2 pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared with young subjects and C ax was unchanged. 

P450 system Concomitant use of SSRIs with drugs metabolized by cytochrome P4502D6 may require lower doses than usually prescribed for either paroxetine or the other drug because paroxetine may significantly inhibit the activity of this isozyme. 

Concomitant use with potential CYP2D6 inhibitors - During coadministration of potential CYP2D6 inhibitors such as quinidine, fluoxetine, or paroxetine with aripiprazole, reduce the aripiprazole dose to at least one-half of its normal dose. 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

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