Treating delusional depressives with amitriptyline

Thirty-five delusional depressed patients were treated for either 28 or 35 days with amitriptyline. The 12 responders could not be differentiated from the nonresponders on a variety of demographic and clinical characteristics. Patients with amitriptyline+nortriptyline plasma levels above 250 ng/ml were significantly more likely to be responders than were patients with levels below that value (p less than .05). A review of the relevant literature revealed that, although some delusional depressives do respond to treatment with tricyclic antidepressants, the presence of delusions is a predictor of poor response to tricyclic antidepressants.     

Grapefruit juice as a contraindication? An approach in psychiatry

The authors investigated in this preliminary study the influence of grapefruit juice on the metabolism of two tricyclic antidepressants. An increase of plasma concentrations is observed indeed for many drugs when administered concomitantly with grapefruit juice. This effect was mainly attributed to inhibition of cytochrome P450 1A2 and 3A4 enzymes by naringenin. These isoenzymes are involved too in the metabolism of many psychotropic drugs. Only two benzodiazepines (midazolam and triazolam) were studied in the conditions of grapefruit juice association. All these studies are performed in healthy subjects and with a study design very different from the clinical conditions. On the basis of these considerations, the authors hypothesized that grapefruit juice should inhibit tricyclic antidepressant metabolism and thus increase the bioavailability of these drugs. They want to precise if this possible drug plasma level increase could be clinically important for depressed patients. Fourteen depressed inpatients were selected for the study. Seven of them received amitriptyline (100 to 150 mg/d) and the seven others clomipramine (112.5 to 225 mg/d). Tricyclic antidepressant and desmethylated metabolite plasma levels were determined on four occasions. The first and second day samples were obtained to determined the plasma level intraindividual variability of antidepressants. On the third and fourth days, plasma levels were determined after an oral coadministration of the antidepressant and 250 ml of pure and fresh grapefruit juice. One patient was excluded from the study due to the coadministration of clomipramine and fluvoxamine. There is indeed a major drug-interaction between these two drugs, and the tricyclic antidepressant plasma levels of this patient were in the toxic range, without side effect. In this group of patients, there was no metabolic interaction between amitriptyline and grapefruit juice. But the mean plasma levels of clomipramine and desmethylclomipramine increased after coadministration of this juice (+4.5% and +10.5% respectively). The authors concluded that with these preliminary results, the potential clinical relevance of this interaction cannot be estimated.     

Amitriptyline and nortriptyline plasma levels, urinary 3-methoxy-4-hydroxyphenylglycol and clinical response in depressed women

Thirty-eight depressed female inpatients, treated intramuscularly with 100 mg/day amitriptyline (AMT), were monitored to investigate the relationships between plasma levels of the drug and its metabolite nortriptyline (NT), the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), side effects and clinical response. Considering the whole group, the clinical improvement was better within an intermediate range of AMT plus NT plasma concentrations (100-200 ng/ml). A more favorable outcome was also observed at NT plasma levels below 55 ng/ml. No significantly different percent clinical response among the patient clinical subgroups was observed as well as no significant correlations between MHPG decrease and drug plasma levels.     

Plasma levels of tricyclic antidepressants and clinical efficacy: review of the literature -- part II

The authors have critically reviewed the literature regarding the relationship between plasma levels of tricyclic antidepressant and their clinical efficacy. When available, drug-drug interactions, pharmacokinetics, and other factors influencing plasma levels of tricyclic antidepressants are discussed. Although many studies are confounded by significant methodological and statistical problems, it appears to these reviews that the available evidence suggests a curvilinear relationship between nortriptyline plasma levels and antidepressant efficacy in tricyclic responsive endogenously depressed inpatients, with maximal therapeutic efficacy achieved with notriptyline plasma levels between 50-175 ng/ml. The evidence for imipramine supports a linear relationship between plasma levels of imipramine plus desmethylimipramine and clinical response in nondelusional endogenously depressed tricyclic responsive inpatients. For amitriptyline, the picture is less clear. However, with the exception of one well-controlled study, the available evidence suppprts some significant relationship between amitriptyline plus nortriptyline plasma levels and antidepressant efficacy in tricyclic respoonsive endogenously depressed patients, but it is not clear as to whether this is a linear relationship or a curvilinear one. For the other antidepressants: protriptyline, desmethylimipramine, doxepin, clomipramine, maprotiline, and butriptyline, a significant relationship (if any) awaits further elucidation. It is important to point out that these plasma level relationships probably do no generalize to other types of depressions (e.g. neurotic, characterological, delusional, acute situationa, etc.) and clearly do not apply to every endogenous tricyclic responsive patient. /owever, it appears that, in general, a clinician will obtain therapeutic efficacy for endogenously depressed patients if these guidelines are followed. The actual therapeutic levels will depend on the assay's sensitivity and specificity and may vary from center to center, illustrates the importance of each center defining its own therapeutic limits, or conversely all centers adoptina a universal reproducible assay methodology for each compound measured. Despite these limitations, these reviewers feel that routine monitoring of plasma levels of the tricyclic antidepressants is a useful method to maximize therapeutic efficacy and prvent undue side effects, as well as to insure good medication compliance.     

Plasma levels, psychophysiological variables, and clinical response to amitriptyline

Hamilton depression scale ratings and physiological measurements were made for 37 patients with primary depression before treatment with amitriptyline (150 mg/day) and again after 2 and 4 weeks of treatment; plasma drug levels were determined weekly. Improvement was maximal at mean amitriptyline + nortriptyline concentrations of 125-200 ng/ml (14 patients), while at lower levels the outcome was significantly poorer (12 patients). Highly variable results were seen in 11 patients with levels between 200 and 301 ng/ml, with lesser improvement occurring in those patients who exhibited poor habituation of the skin resistance response before treatment. Other psychophysiological variables showed significant changes during treatment, but no correlation with clinical results or drug levels.     

Relationship of free nortriptyline levels to therapeutic response

The relationship between the free plasma concentration of nortriptyline and therapeutic response was examined. Eighteen depressed inpatients were treated for 21 days with steady state total nortriptyline plasma concentrations between 50-150 ng/ml. Steady state free nortriptyline concentrations were measured. The therapeutic nortriptyline response was measured by administering the Hamilton and the Carroll Rating scales at day zero and day 21. Statistical relationships between free levels of drug and clinical response were found to be insignificant. Qualitative assessment of the data suggest that free serum levels of nortriptyline in excess of 10 ng/ml may have an inhibitory effect on clinical response.     

Amitriptyline versus placebo in postherpetic neuralgia

To study the effects of amitriptyline in treating postherpetic neuralgia, 24 patients were randomly assigned to either drug or placebo in a double-blind crossover study. We found good to excellent pain relief in 16 of 24 patients (p less than or equal to 0.001). We did not find an antidepressant effect in most patients (p greater than 0.05). The median dose of amitriptyline was 75 mg. The median blood level was 65 ng per milliliter, and of nortriptyline 30 ng per milliliter. Good responses were maintained in 12 of 22 patients. Amitriptyline is useful in treating postherpetic neuralgia and may not act as an antidepressant.     

Rapid response of a disorder to the addition of lithium carbonate: panic resistant to tricyclic antidepressants

There is evidence that panic disorder and major depression might share some common neurobiological factors. This would be consistent with the fact that most antidepressant drugs are effective in preventing panic attacks. This is a case report of a 40 year old woman who was suffering from a panic disorder. Following the discontinuation of a long-term lorazepam treatment, she developed severe depressive symptoms. The depressive syndrome improved rapidly with amitriptyline (150 mg/day), but the panic attacks persisted. Twelve weeks later, amitriptyline was replaced by clomipramine (150 mg/day), the dosage of which was increased to 225 mg/day three weeks later. The patient remained anxious with no resolution of her panic attacks. Two weeks later, lithium carbonate (900 mg/day) was added to clomipramine. Sixty hours later, a dramatic improvement was observed. The lithium plasma level was 0.8 mEq/L. Because of some tremors, lithium was discontinued five days later. Within four days, the anxiety as well as the panic attacks reappeared. Lithium carbonate (600 mg/day) was then resumed. Forty-eight hours later, the patient was showing a clinical improvement similar to that observed following the first addition of lithium. She remained symptom free with the maintenance of the drug combination. To date, several reports have confirmed the beneficial effect of adding lithium to a tricyclic antidepressant drug in resistant major depression. However, we believe that the present case report is the first one documenting the augmentation of a tricyclic antidepressant drug by lithium in a patient suffering from a panic disorder.     

Comparison of efficacy and safety between individualized and empiric dose regimen of amitriptyline in the treatment of major depressive episode

The most efficient method for amitriptyline dose individualization has not been established as yet. For this purpose the authors developed and clinically assessed the modified Bayesian method supported by original basic computer program. Twenty-one male and 39 female subjects (32-65 years old), with major depressive disorder (International Classification of Diseases, 10th revision), were randomly assigned and single-blinded to take individualized (experimental group, n = 30) or empiric (control group, n = 30) doses of amitriptyline for 8 weeks. Both treatments were effective. However, the mean daily doses (112.25 +/- 29.85 vs 124.50 +/- 32.25 mg/day) and plasma concentrations of amitriptyline plus nortriptyline (145.43-161.95 vs 157.63-197.84 ng/mL) were lower in the experimental group (P < 0.05). Total Hamilton Rating Scale for Depression scores at baseline, 14th, 28th, 42nd and 56th day were significantly lower in experimental (mean +/- SD: 26.73 +/- 3.92, 18.73 +/- 4.01, 11.76 +/- 4.43, 9.73 +/- 3.89, 8.60 +/- 3.72) than in control patients (27.56 +/- 4.28, 20.23 +/- 4.23, 14.56 +/- 3.96, 11.56 +/- 4.06, 10.70 +/- 4.30). Clinical Global Impression Scale severity of illness scores in the experimental (5.76 +/- 0.62, 4.90 +/- 0.84, 3.53 +/- 1.30, 2.53 +/- 1.30, 2.10 +/- 1.32) and the control group (5.96 +/- 0.80, 5.03 +/- 0.80, 4.33 +/- 0.92, 3.26 +/- 1.20, 2.83 +/- 1.41), as well as global improvement and therapeutic effect scores, also favored individualized regimen. The adverse effects were less frequent in the experimental group. It is concluded that the modified Bayesian method is more effective and safe than empiric treatment.     

A double-blind comparison study of nomifensine and imipramine in treating depressed patients

Nomifensine was compared to imipramine in treatment of 40 patients with endogenous major depressive disorder. After one week washout, patients were randomly assigned to 5 weeks treatment with Nomifensine or Imipramine. Mean scores for HAM-D, HAM-A, GAS were significantly improved in both treatment groups (P less than 0.01). Two agents were similar in antidepressant efficacy and rapidity of action. Nomifensine treatment group had fewer side effect, whereas the Imipramine group had more adverse experiences. Effects of Nomifensine on the ECG were compared to those of imipramine. Both drugs increased heart rate. Nomifensine less than imipramine. QT measurement interval revealed a statistically significant decrease in imipramine group. Plasma Nomifensine and imipramine concentrations were not correlated with clinical response, side effects or electrocardiographic parameters. The steady-state plasma concentration 105 +/- 47ng/ml for nomifensine, 860 +/- 773ng/ml for imipramine were offaimed respectively at the fixed dose (225mg/day) during the 35 treatment day.     

Studies on 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG) levels in human urine, plasma and cerebrospinal fluids, and their significance in studies of depression

Both concentrations of total 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG) in the human urine, plasma and CSF were determined with a high-pressure liquid chromatography with electrochemical detection in order to clarify the dynamic change in these noradrenaline metabolites. Three different biological fluids were collected simultaneously from 16 orthopedic patients who were regarded clinically as substitutes for normal subjects. In the urine, the MHPG concentrations were 1.67 +/- 0.65 micrograms/mg creatinine (mean +/- S.D.) and DHPG 0.39 microgram/mg creatinine +/- 0.21. The plasma levels were 21.16 ng/ml +/- 9.58 for MHPG, and 19.58 ng/ml +/- 8.13 for DHPG. The CSF levels of MHPG and DHPG were 24.08 ng/ml +/- 8.10 and 34.76 ng/ml +/- 11.46, respectively. The CSF levels of these metabolites were correlated significantly with those in the plasma (r = 0.852, p less than 0.001 for MHPG; r = 0.799, p less than 0.001 for DHPG), while no significant correlations were found between the urinary levels and either the plasma or CSF levels of these metabolites. In the urine, the MHPG levels were proportional to the DHPG levels, while the former were inversely proportional to the latter in the plasma or CSF. Neither the MHPG nor DHPG levels in the urine from depressed patients revealed to have any significant correlation with their clinical assessments using the Hamilton Rating Scale Score (HRS). The patients were treated with an antidepressant active selectively on the noradrenergic system, and no significant changes in urinary excretion of these metabolites were observed before and after the drug treatment. These findings suggest that in the case of psychiatric disorders such as depression, these compound levels in the plasma or CSF would provide more important information than those in the urine.     

Imipramine and tinnitus

Although tinnitus is listed among the rare neurologic side effects of tricyclic antidepressants, little is known about its prevalence, mechanism of development, course, and management. A chart review of 475 patients treated with tricyclic antidepressants indicated that tinnitus occurred in about 1% of the patients. The case vignettes of 5 patients who developed tinnitus in the course of imipramine therapy are presented. Each developed tinnitus in the second or third week of treatment with imipramine at daily dosages of 150-250 mg and at combined plasma imipramine-desipramine levels between 200-450 ng/ml. In each patient, tinnitus subsided spontaneously within 2-4 weeks of onset without any specific treatment, even though the daily dosage of imipramine and the plasma tricyclic levels were constant or increased. Possible mechanisms of development of tinnitus and implications for tricyclic antidepressant therapy are discussed.     

Plasma and erythrocyte levels of tricyclic antidepressants in depressed patients.

Plasma and red blood cells (RBCs), amitriptyline, nortriptyline, imipramine, desipramine, doxepin, and desmethyl doxepin levels were measured in depressed inpatients during steady-state kinetics. A strong positive correlation between the drug levels in plasma and RBCs was found for amitriptyline, nortriptyline, desipramine, and desmethyl doxepin. However, at a given plasma level, up to a 6-fold interindividual variation in the RBC drug levels was found. The correlations between plasma and RBC imipramine and doxepin levels were low. The interindividual variation in the RBC-plasma tricyclic level ratios was large enough to warrant further clinical studies on the relationship between efficacy and pharmacokinetics of tricyclic antidepressants.     

Sildenafil, a phosphodiesterase type 5 inhibitor, enhances the antidepressant activity of amitriptyline but not desipramine, in the forced swim test in mice

The cholinergic theory of depression highlights the involvement of muscarinic acetylcholine receptors in the neurobiology of mood disorders. The present study was designed to investigate the effect of sildenafil, a phosphodiesterase type 5 inhibitor which exhibits cholinomimetic properties, alone and in combination with scopolamine in the forced swim test in mice. Moreover, we assessed the ability of sildenafil to modify the antidepressant activity of two tricyclic antidepressants with distinct cholinolytic activity, amitriptyline and desipramine. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. To evaluate the potential pharmacokinetic interaction between amitriptyline and sildenafil, brain and serum concentrations of amitriptyline were determined by HPLC. Sildenafil (1.25-20 mg/kg) as well as scopolamine (0.5 mg/kg) and its combination with sildenafil (1.25 mg/kg) did not affect the total immobility time duration. However, joint administration of scopolamine with sildenafil at doses of 2.5 and 5 mg/kg significantly reduced immobility time as compared to control group. Moreover, co-administration of scopolamine with sildenafil at the highest dose (5 mg/kg) significantly decreased immobility time as compared to scopolamine-treated group. Sildenafil (1.25, 2.5 and 5 mg/kg) significantly enhanced the antidepressant activity of amitriptyline (5 mg/kg). No changes in anti-immobility action of desipramine (20 mg/kg) in combination with sildenafil (5, 10 and 20 mg/kg) were observed. Sildenafil did not affect amitriptyline level in both brain and serum. In conclusion, the present study suggests that sildenafil may enhance the activity of antidepressant drugs which exhibit cholinolytic activity.     

The impact of CYP2D6 genotypes on the plasma concentration of paroxetine in Japanese psychiatric patients

The authors investigated the impact of the CYP2D6 genotypes on the plasma concentration of paroxetine (PAX) in 55 Japanese psychiatric patients. They were administered 10 to 40 mg/day (24+/-10.0 mg/day) of PAX and maintained at the same daily dose for at least two weeks to obtain the steady-state concentrations. The plasma levels of PAX were 15.8+/-15.0, 47.4+/-32.0, 101.2+/-59.9 and 177.5+/-123.6 ng/ml at the daily dose of 10, 20, 30 and 40 mg, respectively, which suggested dose dependent kinetics of PAX. The allele frequencies of the CYP2D65, CYP2D610 and CYP2D641 were 1.8%, 41.8% and 1.8%, respectively. Significantly higher PAX concentrations were observed in the patients having one functional allele compared with those with two functional alleles (150.9+/-20.6 vs. 243.6+/-25.2 ng/ml mg(-1) kg(-1), p<0.05, Newman-Keuls multiple comparison test) or no functional (243.6+/-25.2 vs. 76.7+/-6.1 ng/ml mg(-1) kg(-1), p<0.05, Newman-Keuls multiple comparison test) in the subjects with 30 mg/day of paroxetine. The same trend of findings as in the subjects treated with 30 mg/day were observed in the subjects with 40 mg/day of PAX. The present results suggest that having one non-functional allele is the marker for high plasma concentration of PAX when relatively high daily dose of PAX is administered.     

Some effects of chronic antidepressant treatments on rat brain monoaminergic systems

Summary A range of established and putative antidepressant therapies were studied for the effect of their long-term administration on two facets of presynaptic monoaminergic functioning in rat brain, namely NE, DA, and 5-HT turnover and alpha₂-adrenoceptor sensitivity. Unless stated otherwise drugs (10 mg/kg) were injected i.p. twice daily for 14 days. ECT (100 mA for 1 s) was applied once daily for 10 days.Changes in turnover were indirectly assessed by measuring levels of metabolites. Brain levels of MHPG-SO₄ were unchanged by chronic amitriptyline, imipramine, nisoxetine (20 mg/kg), nortriptyline, salbutamol (5 mg/kg), and ECT. Amitriptyline elicited a slight, but significant, increase in brain DOPAC content. Brain levels of 5-HIAA were increased by amitriptyline, imipramine, salbutamol, and ECT. An overall view of the results indicates that no common pattern of change was elicited by the range of antidepressant therapies studied.Central alpha₂-adrenoceptor sensitivity was assessed by investigating the effect of various therapies on the ability of clonidine (25g/kg i.p.) to decrease rat brain MHPG-SO₄ content. The clonidine-induced fall was attenuated by desipramine, imipramine, and ECT. Amitriptyline, iprindole, mianserin, nisoxetine, nortriptyline, Org 6582 (10 mg/kg once daily), pargyline (25 mg/kg once daily), salbutamol, and trazodone were ineffective.The following chronic antidepressant therapies were investigated for their effect on rat frontal cortex³H-clonidine binding: amitriptyline, desipramine, imipramine, iprindole, mianserin, nisoxetine, nortriptyline, pargyline, salbutamol, and ECT. Chronic, but not acute, pargyline decreased³H-clonidine binding and this was due to a diminished number of binding sites.The induction of subsensitive presynaptic alpha₂-adrenoceptors in rat brain is not a property common to all forms of antidepressant therapies. Hence it cannot be the fundamental mode of action of antidepressants. No correlation exists between the changes in rat cortical³H-clonidine binding and the observed changes in the sensitivity of central presynaptic alpha₂- adrenoceptors.     

Electrochemically stimulated release of luteinizing hormone and ovulation after surgical interruption of lateral hypothalamic connections in the rat

Plasma LH and FSH were studied in adult female rats following bilateral electrochemical stimulation (ECS) of the medial preoptic area (MPOA). By stereotaxic surgery frontal (FC) and frontal-lateral (LFC) retrochiasmatic "deafferenting" cuts were made with a Halász knife (1.5 mm radius). At 3 and 10 weeks after surgery rats were given pentobarbital (32 mg/kg, i.p.) at 13:30h and stimulated at 15:00h with anodal direct current (20 muA for 60 sec) via concentric bipolar steel electrodes placed bilaterally 0.9 mm from the midline. Stimulation at 3 weeks after FC increased plasma LH from a prestimulation level of 95 +/- ng/ml to 227 +/- 51 ng/ml 80 min after ECS, from which it fell to 111 +/- 29 ng/ml at 160 min, with 2 of 7 animals ovulating the next day. LFC females had similar pre-ECS plasma LH levels 3 weeks after surgery (71 +/- 10 ng/ml), but LH concentrations at 80 min (104 +/- 21 ng/ml) and 160 min post-ECS were significantly lower than those of FC rats, and 0 of 5 rats ovulated. Following a similar protocol 10 weeks after surgery, stimulating the MPOA resulted in comparable elevations in plasma LH and 4 of 10 FC animals ovulated; however, the LFC group still retained a significant blocking effect on ovulation (only 1 of 12 ovulated) when compared with controls the next day. Plasma FSH concentrations were not significantly altered by MPOA stimulation at the parameters employed, either before or after deafferentation. However, LFC resulted in reduced ovarian and uterine weights when compared with controls at both 3 and 10 weeks, whereas FC exerted no observable effect on these organs at these intervals of study. The results of these studies suggest that lateral input to the media basal hypothalamus contributes to MPOA mediated release of LH and ovulation as well as to tonic maintenance of ovarian and uterine function.     

A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report

OBJECTIVE: Few controlled studies have addressed the issue of which antidepressant medications should be recommended for outpatients who have not responded to multiple treatment trials. This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant (nortriptyline) following two prospective, consecutive, unsuccessful medication treatments for nonpsychotic major depressive disorder. METHOD: Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks (first step) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone (second step), adult outpatients (N=235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine (up to 60 mg/day) (N=114) or nortriptyline (up to 200 mg/day) (N=121). The primary outcome, symptom remission, was defined a priori as a total exit score of /=50% reduction in score from baseline). RESULTS: For mirtazapine, remission rates were 12.3% and 8.0% per the Hamilton and QIDS-SR(16) scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS-SR(16) response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Neither response nor remission rates statistically differed by treatment, nor did these two treatments differ in tolerability or adverse events. CONCLUSIONS: Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials resulted in low remission rates (<20%) among patients with major depressive disorder.     

Plasma concentrations of risperidone and olanzapine during coadministration with oxcarbazepine

PURPOSE: Oxcarbazepine (OZC) is a second-generation antiepileptic drug (AED) that also may be used as a mood stabilizer. Unlike carbamazepine (CBZ), which is an inducer of the cytochrome P-450 isoforms and may accelerate the elimination of several therapeutic agents, OXC seems to have only a modest inducing action. The aim of this investigation was to evaluate the effect of a treatment with OXC on plasma concentrations of the new antipsychotics risperidone and olanzapine. METHODS: OXC, at a dosage of 900-1,200 mg/day, was administered for 5 consecutive weeks to 25 outpatients, 10 men and 15 women, aged 25 to 64 years, with bipolar or schizoaffective disorder. Twelve patients were stabilized on risperidone therapy (2-6 mg/day) and 13 on olanzapine (5-20 mg/day). Steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) and olanzapine were measured by high-pressure liquid chromatography (HPLC) before addition of OXC and after 5 weeks from the start of adjunctive treatment. RESULTS: OXC caused only minimal and no significant changes in the mean plasma levels of risperidone (from 5.6 +/- 3.6 ng/ml at baseline to 4.8 +/- 2.6 ng/ml at week 5), 9-OH-risperidone (from 23.6 +/- 7.5 to 24.7 +/- 7.4 ng/ml), and olanzapine (from 26.5 +/- 5.7 ng/ml at baseline to 27.8 +/- 5.1 ng/ml). OXC coadministration with either risperidone or olanzapine was well tolerated. CONCLUSIONS: Our findings indicate that OXC does not affect the elimination of risperidone and olanzapine, thus confirming its weak inducing effect on hepatic drug-metabolizing enzymes.     

Effect of age and gender on citalopram and desmethylcitalopram steady-state plasma concentrations in adults and elderly depressed patients

The effect of aging on steady-state plasma concentrations of citalopram (CIT) and desmethylcitalopram (DCIT) was investigated in 128 depressive patients treated with 10-80 mg/day CIT. They were separated into three groups, with age up to 64 years (mean age+/-S.D.: 47+/-12 years; n=48), between 65 and 79 years (72+/-1 years; n=57), and from 80 years or older (84+/-1 years; n=23). Body mass index (BMI), renal and hepatic functions were similar in the three groups. A large interindividual variability of plasma levels of CIT (16-fold) and DCIT (12-fold) was measured for a given dose. The mean plasma levels of CIT corrected for a 20 mg daily dose were 55% higher in the very elderly (>=80 years) patients (65+/-30 ng/ml; p<0.001) and 38% higher in the elderly (65-79 years) patients (58+/-24 ng/ml; p<0.001) when compared to the adult patients (42+/-17 ng/ml). DCIT mean plasma level was 38% higher (p<0.05) in the group of very elderly patients (22+/-10 ng/ml) when compared to the adult patients (16+/-9 ng/ml). As a consequence, the mean plasma concentration of CIT+DCIT was 48% higher in the very elderly patients (86+/-36 ng/ml; p<0.001) and 33% higher in the elderly patients (77+/-28 ng/ml; p<0.001) when compared to the adult patients (58+/-21 ng/ml). Age correlated significantly with CIT (r=0.43, p<0.001), DCIT (r=0.28, p<0.01), and CIT+DCIT plasma levels (r=0.44, p<0.001), and thus accounts for 18% of the variability of CIT plasma levels, with no influence of gender. The recommended dose reduction of CIT in elderly patients seems therefore justified.