Dose Of Nefazodone Research Articles

Nefazodone reduces dyskinesia, but not psychosis-like behaviours, in the parkinsonian marmoset.

Nefazodone is an anti-depressant that interacts with a wealth of pharmacological targets, including some that may exert anti-dyskinetic and anti-psychotic effects in Parkinson's disease (PD), notably serotonin 1A and 2A receptors. In this study, we sought to determine the effect of nefazodone on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Six common marmosets developed parkinsonism following administration of MPTP, after which they were treated chronically with L-DOPA to induce stable dyskinesia and PLBs. In behavioural experiments, nefazodone (0.01, 0.1 and 1mg/kg) or vehicle was administered in combination with L-DOPA and its effects on dyskinesia, PLBs and parkinsonian disability were assessed. The addition of nefazodone 0.01, 0.1 and 1mg/kg to L-DOPA reduced the severity of peak dose dyskinesia by ≈ 21%, ≈ 39% and ≈ 42% (all P < 0.05), while it did not have any significant effect on PLBs, when compared to L-DOPA/vehicle. Parkinsonian disability was not affected by any dose of nefazodone. Our results suggest that nefazodone may be effective to alleviate L-DOPA-induced dyskinesia in PD, while it may not exert any beneficial effect on dopaminergic psychosis.

Breastfeeding women with depression: Maternal and infant well-being

Background To examine the well-being of depressed, breastfeeding women treated with antidepressants (G1), and their infants, for the first year postpartum, compared to those who forgo pharmacotherapy (G2), and to healthy, breastfeeding women (G3). Methods Women-infant pairs were followed-up at 4, 13, 26, 39, and 52 weeks postpartum. The Edinburgh Postnatal Depression Scale (EPDS), Short Form 36 (SF-36), and the Functional Status II Revised (FS-IIR) were used to measure maternal depression, well-being, and infant well-being. Results Fifty-six, 32, and 59 women in G1, G2, and G3, respectively completed all follow-ups. The only adverse event associated with antidepressant exposure through breast milk was 1 infant with increased bowel movements following maternal nefazodone dose increases. Although EPDS scores improved over time in all groups, 9 and 31% of women in G1 and G2 respectively were still scoring above 12 at 52 weeks. G2 women had statistically lower SF-36 mental component scores compared to G3 (G1 47.6, G2 42.4, G3 54.6, p<0.01). There were no differences in SF-36 physical component scores. G1 infants scored statistically lower in FS-IIR total and health scores compared to G3. Conclusions Although FS-IIR scores were lower, only 1 infant had minor adverse effects associated with maternal antidepressants. Many women on antidepressants were not adequately treated. Women requiring antidepressants postpartum should continue to breastfeed and be adequately dosed to control their depression. Clinical Pharmacology & Therapeutics (2005) 77, P29–P29; doi: 10.1016/j.clpt.2004.12.003

Effect of the antidepressant nefazodone on the density of cells expressing mu-opioid receptors in discrete brain areas processing sensory and affective dimensions of pain.

The principal use of antidepressants is in the treatment of depression and affective disorders. Antidepressants have also been used as an adjuvant to analgesics in pain treatment. However, in chronic treatment, their antinociceptive and antidepressive effects coexist simultaneously. Antidepressants can interact with the opioid system, which is also involved in regulating nociceptive processing and affective state. Chronic antidepressants could act by increasing mu-opioid receptor expression in many brain areas involved in the regulation of nociception and affective state. The aim of this study was to evaluate the antinociceptive and antidepressant-like effects and the possible variations in mu-opioid receptor expression induced by a chronic nefazodone treatment in brain areas related to pain and affective state. Wistar rats were chronically treated with nefazodone (10 and 25 mg/kg IP, twice a day, for 14 days). Twelve hours after the last day 14 dose of nefazodone, a tail-flick test was performed. After the administration of a daily dose of nefazodone, Porsolt's test was carried out 12 h after last dose. Two hours after completion of 14 days treatment, other animals were processed for mu-opioid receptor immunocytochemistry using polyclonal antisera raised in rabbits. Several brain regions were analyzed: the frontal and cingulate cortex, the dorsal raphe nucleus and the periaqueductal gray. Chronic nefazodone treatment induced a significant increase in tail-flick latency and a significant decrease in immobility time at total doses of 20 and 50 mg/kg per day ( P<0.05). In treated animals, the density of neural cells immunostained for mu-opioid receptor in the frontal and cingulate cortices, dorsal raphe nucleus and periaqueductal gray had increased after chronic nefazodone compared to controls. Therefore, chronic nefazodone induces antinociceptive and antidepressant-like effects in rats and increases mu-opioid receptor expression in brain areas related to pain and affective state. These results suggest that antidepressants could be effective on somatic and affective dimensions of pain and this action could be related to its influence on the opioid system.

Nefazodone in the rat: mimicry and antagonism of [−]-DOM-induced stimulus control

Nefazodone is presently marketed as an antidepressant that inhibits both serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake while antagonizing pirenpirone (5-HT 2) receptors. This 5-HT receptor type is believed to play a prominent role in the underlying mechanism of action of serotonergic hallucinogens. Antidepressant medications now represent the most commonly prescribed psychoactive medications in the world and are likely to be ingested in the presence of hallucinogens with increased frequency; the consequences are largely unknown. The present investigation examined the interaction between the serotonergic phenethylamine hallucinogen [−]-2,5-dimethoxy-4-methylamphetamine ([−]-DOM), and nefazodone, in rats trained with [−]-DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. The data indicate that maximal substitution of nefazodone for the [−]-DOM stimulus was present using a 45-min pretreatment time before testing. Using this pretreatment time, a dose of nefazodone of 12.0 mg/kg administered alone resulted in 76% DOM-appropriate responding. When a range of doses of nefazodone was combined with the training dose of [−]-DOM, a pattern of responding compatible with partial agonism was observed. The intermediate degree of [−]-DOM generalization to nefazodone was significantly antagonized by the 5-HT antagonists, 5-HT 2, SR 46349B (5HT 2A/2C), and M100907 (5-HT 2A). Taken together, the present data suggest that (a) nefazodone acts as a partial agonist and (b) these effects are mediated by the 5-HT 2A receptor.

Carbamazepine-nefazodone interaction in healthy subjects.

The pharmacokinetic interaction between nefazodone and carbamazepine was investigated in 12 healthy male volunteers. Subjects received nefazodone 200 mg twice daily for 5 days, and blood sample collection was performed on day 5 for 0- to 48-hour pharmacokinetic analysis. A 4-day wash-out phase then followed from days 6 to 9. Carbamazepine 200 mg was administered once daily from days 10 to 12, and then 200 mg was given twice daily from days 13 to 44. A 0- to 48-hour pharmacokinetic analysis was performed on day 38. Nefazodone 200 mg twice daily was added to the dosing regimen from days 40 to 44, and a subsequent 0- to 48-hour pharmacokinetic analysis was performed on day 44. Coadministration of nefazodone increased steady-state plasma area under the concentration-time curve (AUC) of carbamazepine from 60.77 (+/-8.44) to 74.98 (+/-12.88) microg x hr/mL (p < 0.001) and decreased the active carbamazepine-10,11-epoxide metabolite AUC concentration from 7.10 (+/-1.16) to 5.71 (+/-0.52) microg x hr/mL (p < 0.005). During the combination, the steady-state AUC of nefazodone decreased from 7,326 (+/-3,768) to 542 (+/-191) ng x hr/mL, and the AUCs of its metabolites (hydroxynefazodone, meta-chlorophenylpiperazine, and triazoledione) decreased significantly as well (p < 0.001). Coadministration of nefazodone 200 mg twice daily and carbamazepine 200 mg twice daily was found to be safe and well tolerated; however, the increased plasma exposure to carbamazepine may warrant monitoring of plasma carbamazepine concentrations with the combination. However, higher doses (>400 mg/day) of carbamazepine could yield more extensive induction, affecting tolerability of the combination. No change in the initial nefazodone dose is necessary, and subsequent dose adjustments should be made on the basis of clinical effects; however, the repercussion of carbamazepine induction of nefazodone metabolism on the antidepressant efficacy has yet to be studied.

The effects of single dose nefazodone and paroxetine upon 5-HT2A binding potential in humans using [18F]-setoperone PET.

Alterations in 5-HT2A receptor binding are implicated in suicidality and depression. 5-HT2A receptors may also be involved in the therapeutic effects of antidepressants. The purpose of this study was to assess the effect of paroxetine and nefazodone on 5-HT2A receptors after a single dose. Seven subjects received a single dose of nefazodone 200 mg and five subjects received a single dose of paroxetine 20 mg. Before and after the dose, 5-HT2A binding potentials (Bmax/Kd) were determined in each subject using [18F]-setoperone PET. Nefazodone induced a significant change in 5-HT2A binding potential (-39+/-17%,, P = 0.003) while paroxetine showed no significant alteration of 5-HT2A binding potential (+3+/-13%, P = 0.73). The change in 5-HT2A binding potential seen with nefazodone represents blockade of 5-HT2A receptors by the drug. We do not find evidence for acute downregulation of 5-HT2A receptors with paroxetine within 9 h.

Clinical pharmacokinetics of nefazodone.

Nefazodone is a new antidepressant drug, chemically unrelated to the tricyclic, tetracyclic or selective serotonin uptake inhibitors. Nefazodone blocks the serotonin 5-HT2 receptors and reversibly inhibits serotonin reuptake in vivo. Nefazodone is completely and rapidly absorbed after oral administration with a peak plasma concentration observed within 2 hours of administration. Nefazodone undergoes significant first-pass metabolism resulting in an oral bioavailability of approximately 20%. Although there is an 18% increase in nefazodone bioavailability with food, this increase is not clinically significant and nefazodone can be administered without regard to meals. Three pharmacologically active nefazodone metabolites have been identified: hydroxy-nefazodone, triazoledione and m-chlorophenylpiperazine (mCPP). The pharmacokinetics of nefazodone are nonlinear. The increase in plasma concentrations of nefazodone are greater than would be expected if they were proportional to increases in dose. Steady-state plasma concentrations of nefazodone are attained within 4 days of the commencement of administration. The pharmacokinetics of nefazodone are not appreciably altered in patients with renal or mild-to-moderate hepatic impairment. However, nefazodone plasma concentrations are increased in severe hepatic impairment and in the elderly, especially in elderly females. Lower doses of nefazodone may be necessary in these groups. Nefazodone is a weak inhibitor of cytochrome P450 (CYP) 2D6 and does not inhibit CYP1A2. It is not anticipated that nefazodone will interact with drugs cleared by these isozymes. Indeed, nefazodone did not affect the pharmacokinetics of theophylline, a compound cleared by CYP1A2. Nefazodone is metabolised by and inhibits CYP3A4. Clinically significant interactions have been observed between nefazodone and the benzodiazepines triazolam and alprazolam, cyclosporin and carbamazepine. The potential for a clinically significant interaction between nefazodone and other drugs cleared by CYP3A4 (e.g. terfenadine) should be considered before the coadministration of these compounds. There was an increase in haloperidol plasma concentrations when coadministered with nefazodone; nefazodone pharmacokinetics were not affected after coadministration. No clinically significant interaction was observed when nefazodone was administered with lorazepam, lithium, alcohol, cimetidine, warfarin, theophylline or propranolol.

The effect of nefazodone on the single-dose pharmacokinetics of phenytoin in healthy male subjects.

The effect of nefazodone on the pharmacokinetics of a single dose of phenytoin was evaluated in 18 healthy male subjects. The subjects received a single oral dose of phenytoin, 300 mg, on day 1 of the study and the pharmacokinetic profile of the drug was determined. After a washout period followed by oral administration of nefazodone, 200 mg twice daily for 7 days, subjects received a single dose of phenytoin, 300 mg concomitantly with the morning dose of nefazodone on day 12, and the pharmacokinetic profile of phenytoin was determined again. Minimum plasma concentrations of nefazodone and its main metabolites indicated that steady state had been achieved for nefazodone when phenytoin and nefazodone were administered concomitantly. No significant differences were demonstrated between mean single-dose pharmacokinetic parameters of phenytoin when administered alone on day 1 and concomitantly with nefazodone on day 12. Assessment of adverse events, clinical laboratory parameters, electrocardiograms, vital signs, and physical examinations indicated that concomitant administration of nefazodone and phenytoin was safe and well tolerated. These data demonstrate that nefazodone does not affect the single-dose pharmacokinetics of phenytoin, but do not preclude the possibility of such an interaction when phenytoin is administered on a long-term basis. A clinically significant interaction between nefazodone and phenytoin through a pharmacokinetic mechanism is unlikely.

THE LACK EFFECT OF FOOD ON THE BIOAVAILABILITY OF NEFAZODONE TABLETS

The objective of this study was to assess the effect of food on the pharmacokinetics of nefazodone (NEF). A group of 24 healthy adult male volunteers received a single 200 mg dose of NEF under fasting conditions as well as 5 min after a high-fat breakfast. There was a 1 week washout between treatments. Serial blood samples were collected for 48 h after dosing and assayed by a validated HPLC method for NEF and the metabolites hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP), and triazoledione (dione). The mean (SD) peak concentration (Cmax) for NEF was not affected by food and was 416 (220) ng mL−1 and 446 (271) ng mL−1 after the fed and fasted treatments, respectively. The median time to reach Cmax (Tmax ) was also unaffected by food and was 2 h for both treatments. However, the mean (SD) area under the curve (AUC) was significantly reduced by food from 1815 (1017) ng h mL−1 to 1409 (695) ng h mL−1. Although there was an 18% decrease in NEF AUC when administered with food, food had no effect on Cmax and Tmax values for NEF, HO-NEF, mCPP or dione or AUC values for HO-NEF, mCPP, or dione, indicating that NEF can be administered without regard to meals.

Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment.

The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in 12 healthy younger subjects < or = 55 years of age (YNG), 12 elderly subjects > or = 65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis (HEP) and 12 patients with moderate renal impairment (REN), ClCR 20-60 ml.min-1. The study was of parallel group design, with each of the four subject groups receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1 week intervals. Serial blood samples for pharmacokinetic analysis were collected for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and mCPP by a validated HPLC method. Single oral doses up to 200 mg of nefazodone were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP plasma levels were about 1/3 and < 1/10 those of NEF, respectively. There were no apparent gender-related pharmacokinetic differences in any group of subjects. NEF and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a superproportional increase in AUC and an increase in t1/2 with increasing dose was obtained, indicative of nonlinear pharmacokinetics. Relative to normal subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with moderate renal impairment did not. Elderly and cirrhotic patients may require lower doses of NEF to achieve and maintain therapeutic effectiveness.

Steady-state pharmacokinetics of nefazodone in subjects with normal and impaired renal function.

The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in subjects with normal and impaired renal function. The Study was of parallel group design which included 7 subjects with normal (NOR) renal function, CLCR > or = 72 ml.min-1 x 1.73 m-2, 6 with moderate (MOD) renal impairment, CLCR 31-60 ml.min-1 x 1.73 m-2 and 9 with severe (SEV) renal impairment, CLCR < or = 30 ml.min-1 x 1.73 m-2. Subjects in each renal function group received a 100-mg oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR, MOD and SEV, respectively). Single trough blood samples just prior to each morning dose (Cmin) and serial samples after the dose on day 8 were obtained at each dose level for pharmacokinetic analysis. Plasma samples were assayed by a specific HPLC method for NEF, HO-NEF and mCPP. The CMIN data indicated that steady state was attained by the third day of BID administration of both the 100- and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF and HO-NEF attained steady-state Cmax within 2 h after administration of nefazodone; tmax for mCPP was less defined and more delayed. HO-NEF and mCPP plasma levels were about 1/3 and < 1/10 those of NEF, respectively, regardless of the status of renal function. Steady-state systemic exposure of NEF and HO-NEF, as reflected by AUC and Cmax, and elimination t1/2 values did not differ significantly among renal function groups. The study results suggest that dose adjustments may not be necessary, but nefazodone should be used with caution in the presence of severe renal impairment.

Single- and multiple-dose pharmacokinetics of nefazodone in patients with hepatic cirrhosis.

To compare the single- and multiple-dose pharmacokinetics of nefazodone and its three pharmacologically active metabolites, hydroxynefazodone, m-chlorophenylpiperazine, and triazoledione, in patients with biopsy-proven cirrhosis and age-, sex-, and weight-matched healthy volunteers. Subjects received a single 100 mg dose of nefazodone on day 1 followed by 100 mg nefazodone every 12 hours on days 3 through 10. Serial blood samples were collected on days 1 and 10; blood samples for trough levels were also collected just before the morning doses on days 7, 8, and 9. Plasma samples were assayed for nefazodone and its metabolites by validated chromatographic methods. The blood samples for trough levels indicated that, regardless of hepatic function, steady state for nefazodone and its metabolites was achieved by the fourth day of every-12-hour dosing. Subjects with liver cirrhosis had about a two-fold greater systemic exposure to nefazodone and hydroxynefazodone compared with normal subjects after a single dose of nefazodone, the difference decreasing to approximately 25% at steady state. Exposure to m-chlorophenylpiperazine was twofold to threefold greater and exposure to triazoledione was similar in patients with cirrhosis after a single dose of nefazodone and at steady state. There were no serious or unexpected adverse events observed in this study. These findings indicate that, although no untoward accumulation is anticipated compared with patients with normal hepatic function, patients with hepatic impairment may be exposed to higher concentrations of nefazodone and its metabolites than would subjects with normal hepatic function. Consequently, a lower daily dose of nefazodone should be considered when treating patients with impairment of hepatic function.

Coadministration of Nefazodone and Benzodiazepines

This study was conducted to determine the potential for an interaction between nefazodone, a new antidepressant, and triazolam after a single dose of triazolam and multiple doses of nefazodone in a randomized, double-blind, placebo-controlled study in healthy male volunteers. The metabolism of triazolam is dependent on cytochrome P450 3A4, and because nefazodone has been shown in vitro to be an inhibitor of this isoenzyme, this study was conducted to assess the potential for an interaction between the two drugs. Twelve subjects were assigned to one of two groups and received an oral dose of either placebo or 0.25 mg of triazolam on days 1 and 2. Nefazodone (200 mg) was administered twice daily from the evening of day 2 to the morning of day 9. Subjects received either 0.25 mg of triazolam or placebo with the nefazodone dose on the mornings of days 8 and 9. Serial blood samples were collected on the mornings of days 1, 2, 8, and 9 for the analysis of triazolam by a validated gas chromatography/electron capture detection method and on days 8 and 9 for the analysis of nefazodone and its metabolites, hydroxynefazodone (HO-nefazodone) and m-chlorophenylpiperazine (mCPP), by a validated high-performance liquid chromatography/ultraviolet method. Noncompartmental pharmacokinetic analysis showed that there was no effect of triazolam on the pharmacokinetics of nefazodone, HO-nefazodone, or mCPP after the coadministration of triazolam and nefazodone. There was a significant effect of 200 mg of nefazodone twice daily on the pharmacokinetics of triazolam. Mean triazolam peak concentration values increased (p = 0.003) from 2.33 to 3.88 ng/ml when triazolam was administered alone and in combination with nefazodone, respectively. Corresponding mean triazolam area under the curve values increased (p < 0.001) from 8.14 to 31.74 ng.h/ml. The plasma protein binding of triazolam was approximately 85% when triazolam was given alone and when given concurrently with nefazodone. The increase in triazolam concentrations in plasma appears to be attributable to the inhibition of cytochrome P450 3A4 metabolism by nefazodone. If triazolam is coadministered with nefazodone, a reduction in the triazolam dosage is recommended; no dosage adjustment is required for nefazodone.

Safety, Tolerance, and Preliminary Pharmacokinetics of Nefazodone After Administration of Single and Multiple Oral Doses to Healthy Adult Male Volunteers: A Double‐Blind, Phase I Study

Safety, tolerance, and preliminary pharmacokinetics of nefazodone, a new antidepressant, were assessed in a randomized, double-blind, parallel group study carried out in two sequential segments: a single and a multiple daily dose segment. Nine subjects in the single daily dose segment were divided into three treatment groups and received nefazodone doses in a leapfrog fashion. Each day of treatment with nefazodone was followed by 2 days of placebo treatment and then administration of the next higher drug dose. Single doses ranged from 5-500 mg. 8 subjects enrolled in the multiple daily dose segment were divided into two treatment groups. In each group, 3 subjects received nefazodone and one received placebo 3 times a day. Each dosage level was administered for 2 days before proceeding to the next higher dose from 5 mg or 10 mg 3 times a day to a maximum of 500 mg 3 times a day. After the dose-escalation period, the subjects in the multiple daily dose segment underwent a 3-day washout, after which they received a single dose of nefazodone at the maximum tolerated level. Safety and tolerance assessment involved analyses of adverse events, laboratory tests, vital signs, ophthalmic examinations, and ECGs. Blood and urine samples were obtained only in the multiple daily dose segment and analyzed for nefazodone and its two pharmacologically active metabolites, hydroxynefazodone and mCPP. A single blood sample was collected on 8 different days for assessment of trough levels (Cmin) and serial samples were obtained on days 5, 9, and 22 of dosing for pharmacokinetic profiles. Additional serial samples were also obtained after the last single dose of 500 mg after a 3-day washout. Nefazodone was found to be safe and well-tolerated in total daily doses as high as 1350 mg (450 mg 3 times a day). Nefazodone was rapidly absorbed after oral administration and converted to hydroxynefazodone and mCPP. The pharmacokinetics of nefazodone, hydroxynefazodone, and mCPP were found to be dose-dependent, as evidenced by dose normalized values of Cmin, Cmax, and AUC0-8 that progressively increased with dose. Although exposure of normal subjects to nefazodone and its 2 pharmacologically active metabolites was disproportionately higher than the corresponding increase in dose, the safety and tolerance profiles did not show a parallel increase in adverse events. Nefazodone may be well-tolerated by patients receiving expected therapeutic doses from 200-600 mg per day when administered in divided doses every 8 to 12 hours.

Nefazodone in the Treatment of Premenstrual Syndrome

Nefazodone, a new phenylpiperazine antidepressant agent with serotonin type 2 antagonism and serotonin reuptake inhibition, was evaluated in two patient groups to determine its effectiveness in reducing the symptoms of premenstrual syndrome (PMS). The two studied groups were PMS patients with no coexisting major depression or dysthymia (N = 23) and PMS patients with current major depression or dysthymia, termed the premenstrual exacerbation group (N = 24). The two patient groups received open-label nefazodone for 8 weeks, with optional maintenance at the same dose for up to 1 year. The initial dose was 100 mg, titrated to 600 mg/day, on a twice-daily dosing schedule. Symptoms were assessed by the Hamilton Rating Scale for Depression and by Daily Symptom Ratings. Premenstrual symptoms improved significantly from pretreatment baseline values, with similar improvement for the PMS and premenstrual exacerbation groups. Significantly improvement occurred by the end of the first treated cycle (4 weeks of therapy), at an average dose of 245 (range, 100 to 400) mg, and was maintained thereafter. Nefazodone was well tolerated, side effects were often transient, and the most common were nausea and headache. Forty-seven of 54 patients completed 2 months of therapy, with a mean daily nefazodone dose of 319 mg at the 2-month point. A placebo-controlled study should be conducted to confirm and extend these promising preliminary findings.