Effects of zimelidine and desipramine on serotonin and noradrenaline uptake mechanisms in relation to plasma concentrations and to therapeutic effects during treatment of depression

The selective inhibitors of neuronal 5-hydroxytryptamine (5-HT) and noradrenaline (NA) uptake, zimelidine and desipramine, were compared in a double blind crossover study of 40 inpatients with endogenous depression. The clinical effects of these two drugs and some biochemical variables related to the monoamine systems were studied during 4 weeks' treatment. Patients with a low pretreatment level of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) (<20 ng/ml) responded significantly better to zimelidine treatment than those with a high pretreatment level (>20 ng/ml). In the group treated with desipramine no difference in therapeutic outcome was obtained between patients with low and high pretreatments levels of 5-HIAA in the CSF. Attempts to correlate the steady state plasma concentrations of zimelidine, norzimelidine and desipramine with the therapeutic effect were unsuccessful. The plasma concentration of norzimelidine demonstrated a singificant (P<0.05) positive correlation with age. The mean value of the uptake of ¹⁴C-5-HT in the patients' platelets, when measured before the treatment, was significantly (P<0.05) lower than found in a control group. Zimelidine, mainly via its metabolite norzimelidine, caused a pronounced inhibition of uptake of ¹⁴C-5-HT in platelets, decrease in whole blood 5-HT and inhibition of accumulation of ¹⁴C-5-HT in rat hypothalamic synaptosomes incubated in the patients plasma. Desipramine produced a slight inhibition of accumulation of ¹⁴C-5-HT in rat synaptosomes, but a marked inhibition of uptake of ¹⁴C-5-HT in the patient's platelets and a decrease in whole blood 5-HT. The accumulation of ³H-NA in rat synaptosomes incubated in the patients' plasma was strongly inhibited by desipramine treatment but only slighty affected by zimelidine.     

Differential effect of chlorimipramine and nortriptyline on cerebrospinal fluid metabolites of serotonin and noradrenaline in depression

Summary The serotonin and noradrenaline metabolites 5-hydroxyindole-3-acetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenyl glycol (HMPG) were determined in cerebrospinal fluid (CSF) from 18 depressed patients. HMPG levels in CSF decreased significantly when the patients were treated either with chlorimipramine or nortriptyline. 5-HIAA fell from 20.2±7.1 to 11.2±4.9 ng/ml (p<0.001) during chlorimipramine treatment, whereas it was not decreased significantly by treatment with nortriptyline. There was a significant correlation between the CSF concentration of each metabolite before and after treatment. In the seven patients who received nortriptyline the percentage fall of HMPG was more marked than that of 5-HIAA; the converse effect occurred in ten of the eleven treated with chlorimipramine. The relative effects of the two drugs on the CSF levels of 5-HIAA and HMPG were consistent with earlier studies of uptakein vitro and of turnover in animals. Chlorimipramine was a potent inhibitor of the uptake of serotonin, whereas nortriptyline had more influence on noradrenergic mechanisms.     

Plasma levels of zimelidine and norzimelidine in endogenous depression

A new serotonin uptake inhibitor zimelidine was studied in 16 endogenously depressed inpatients, who received 150 mg/day orally during 3–6 weeks in a phase II-type study. Plasma concentrations of zimelidine and its main metabolite norzimelidine were determined twice a week. Ten patients obtained a welldefined steady-state plasma level within 1–2 weeks, while three patients still had increasing concentrations of both substances or only norzimelidine within the investigation period. In two patients, biochemical affection of the liver could be demonstrated during the treatment; one associated with moderate clinical symptoms (dizziness and fever), the other without clinical symptoms. Both patients recovered upon cessation of the zimelidine treatment. In the former patient, very high concentrations of zimelidine at the time of hepatic symptoms were demonstrated, while the latter patient was within the average concentration range. Other adverse reactions were mild and few, particularly with respect to anticholinergic effects. With the applied, probably suboptimal, dosage the therapeutic response was only satisfactory in five cases.     

Inhibition of 5-hydroxytryptamine uptake in human platelets by antidepressant agents in vivo

The accumulation of ¹⁴C-5-hydroxytryptamine (¹⁴C-5-HT) in platelet-rich plasma (PRP) and the concentration of 5-hydroxytryptamine (5-HT) in whole blood of patients treated with the antidepressant agents zimelidine (2×100 mg. daily), desipramine (2×75 mg daily), and clomipramine (2×75 mg daily) were examined before and during the treatment. Clomipramine and zimelidine markedly reduced the accumulation of ¹⁴C-5-HT and the concentration of 5-HT in the blood. Desipramine had a weaker, but significant effect. Added to the PRP in vitro clomipramine was ten-times more potent than norzimelidine, the active metabolite of zimelidine, and 60- and 300-times more active than desipramine and zimelidine, respectively in inhibiting the accumulation of ¹⁴C-5-HT. Analysis of plasma concentrations of zimelidine and norzimelidine showed that the decreased blood 5-HT and the inhibition of ¹⁴C-5-HT accumulation in platelets was mainly produced by norzimelidine. The inhibition of the ¹⁴C-5-HT accumulation and the decrease in blood 5-HT by desipramine were significantly correlated to the log plasma concentration of desipramine. It is concluded that the decrease in blood 5-HT caused by these agents is due to the inhibition of 5-HT uptake in platelets. The half-life of the decrease in blood 5-HT after clompramine and zimelidine was about 5 days. The return to normal 5-HT level after withdrawal of the drugs was 14 days or longer. These observations might indicate that only the newly formed platelets can accumulate 5-HT.     

Pharmacokinetics of zimelidine

Summary The systemic availability of a new antidepressant, zimelidine, and of its pharmacologically active metabolite, norzimelidine, was studied in six healthy male volunteers. Three single doses of zimelidine (25 mg and 100 mg orally and 25 mg i.v.) and two single doses of norzimelidine (25 mg orally and i. v.) were given to each volunteer allowing at least seven days between administrations. Plasma concentrations of zimelidine and norzimelidine were determined in serial blood samples by HPLC. Following oral zimelidine peak plasma concentrations of the metabolite were attained about 3 h after dosing. Oral administration of norzimelidine itself resulted in a plasma concentration profile for this compound that was similar to that observed after oral zimelidine. Utilising the plasma concentration data following intravenous infusion of each compound, the elimination half-lives for zimelidine and norzimelidine were calculated to be 5.1 h (range 4.3–6.0) and 15.5 h (range 10.6–22.9) respectively. The total body clearances of the 2 compounds were similar at 0.52 l · min^–1 (range 0.26–0.70) for zimelidine and 0.56 l · min^–1 (range 0.28–0.83) for norzimelidine. The substantially longer elimination half-life of norzimelidine was apparently the result of a larger volume of distribution (9.4 l · kg^–1; range 7.8–11.4) for this metabolite, as compared to zimelidine (3.21 · kg^–1; range 1.6–4.9). The calculated bioavailability of zimelidine was 26% (range 9.1–39) after the 25 mg oral dose, and 29% (range 14–46) after the 100 mg dose. The bioavailability of norzimelidine was 66% (range 36–91). However, oral administration of zimelidine resulted in as much or more norzimelidine reaching the systemic circulation, as the oral administration of norzimelidine itself. This is important as a large part of the activity of the drug may be due to the metabolite.     

Spinal modulation of acoustic startle: Opposite effects of clonidine and d-amphetamine

The effects of prolonged treatment of rats with zimelidine, 5, 12.5, and 25 mol/kg PO twice daily for 2 weeks, on the accumulation of ¹⁴C-5-hydroxytryptamine (¹⁴C-5-HT) and ³H-noradrenaline (³H-NA) in hypothalamic slices were studied. The concentrations of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in whole brain, the concentration of 5-HT in whole blood and the in vitro labelling of receptors in cerebral cortex with ³H-5-HT, ³H-dihydroalprenolol (³H-DHA) and striatum with ³H-spiroperidol were also determined, and the concentrations of zimelidine and its demethylated metabolite norzimelidine in plasma and hypothalamus were analysed. The degree of inhibition of the accumulation of ¹⁴C-5-HT and ³H-NA was not changed or only slightly increased by prolonged treatment as compared to acute treatment with zimelidine, i.e. the 5-HT accumulation was more inhibited than the NA accumulation. The inhibition of ¹⁴C-5-HT accumulation was significantly correlated to the plasma and hypothalamic concentration of norzimelidine 14 h after the last repeated administration. The 5-HT concentration in whole blood was markedly reduced at the same doses which produced inhibition of 5-HT uptake in brain, which indicates that the inhibition of 5-HT uptake in platelets and in neurons are similarly affected. The concentration of 5-HIAA in whole brain was reduced by both single and repeated administration of zimelidine, whereas the concentration of 5-HT was decreased only after prolonged treatment. The density of -adrenoceptors (binding of ³H-DHA) was significantly reduced by zimelidine, whereas 5-HT receptor binding (³H-5-HT) and dopamine receptor binding (³H-spiroperidol) were unchanged. It is concluded that the effects on 5-HIAA and 5-HT levels in brain and on the -adrenoceptors in cerebral cortex reflect pre-and post-synaptic regulation resulting from the uptake inhibition.     

Assessment of the anticholinergic effects of antidepressants in a single-dose cross-over study of salivation and plasma levels

In order to evaluate the anticholinergic effect of antidepressant drugs, 11 healthy volunteers were given single oral doses of reference drug, test drugs or placebo on a double-blind basis at weekly intervals. The doses corresponded to average daily patient medications. Spontaneous whole mouth and parotid salivation, and plasma levels of drug and possible metabolites were measured 2, 6 and 10h after drug administration.Moderate, statistically significant inhibition of salivation was found when nortriptyline, imipramine-N-oxide and mianserin were given. Less pronounced, but still statistically significant inhibition occurred after ingestion of nomifensine and zimelidine. The zimelidine effect was exclusively due to the metabolite norzimelidine, and the inhibition after imipramine-N-oxide was mainly due to the metabolite imipramine, but imipramine-N-oxide itself also had slight activity. Isocarboxazide and lithium had no effect on salivation.From these results and reported values of pharmacokinetic variables, the average level of anticholinergic activity during long-term treatment may be predicted: for mianserin and (nor-)zimelidine moderate inhibition of salivation, although less pronounced than with nortriptyline; for nomifensine no clinically significant effect; and for imipramine-N-oxide a negligible contribution from the unmetabolized drug.     

Serotonin uptake inhibition during treatment of depression with nortriptyline caused by parent drug and not by 10-hydroxymetabolites

Treatment of endogenous depression with nortriptyline (NT), at a daily dose of 150 mg, resulted in a pronounced improvement of seven of ten patients investigated. The concentration of the norepinephrine metabolite HMPG in cerebrospinal fluid (CSF) decreased by 29% (P<0.01) after 3 weeks of treatment. There was no significant effect of treatment on the serotonin and dopamine metabolites 5-HIAA and HVA. In previous larger materials, however, a decrease of 5-HIAA in CSF has been demonstrated.Platelets from the patients showed an increase in K _m for serotonin uptake in response to NT treatment. The IC₅₀ value of NT for serotonin uptake inhibition was 940 nM, while the corresponding value of the major metabolite of NT, i.e. E-10-OH-NT, was much higher (6700 nM). Thus, during treatment, the parent drug and not the metabolite was responsible for the serotonin uptake inhibition in platelets. There was a close correlation between K _m and the plasma concentration of NT after 1 week of treatment (r=0.88, P<0.01) but not after 3 weeks of treatment (r=0.48; ns). There was no uniform effect of NT treatment on V _max. It is concluded that clinical NT treatment results in uptake inhibition not only in norepinephrine but also in serotonin neurons.     

Platelet serotonin uptake inhibition as a basis for monitoring antidepressant drug treatment

A quantitative method for measuring serotonin uptake inhibition in fresh platelets incubated in diluted plasma (stored frozen until analyzed) from patients treated with tricyclic and related antidepressants is described. The method was used in a clinical trial comparing the specific serotonin uptake inhibitor zimelidine with the mixed serotonin-norepinephrine uptake inhibitor desipramine in patients with endogenous depression, and correlating this with plasma drug concentration assessment. The bioassay, based on the use of one single, low concentration of serotonin, was found to be very sensitive and to have a high reliability (coefficient of variation about 2% as calculated from duplicate samples), and to correlate highly with log plasma concentration of zimelidine, norzimelidine, and of desipramine. This bioassay may have some advantages in relation to plasma drug concentration assessment, but only future studies can show whether it provides a better basis for antidepressant drug monitoring.     

Pharmacokinetics of zimelidine in humans — Plasma levels and urinary excretion of zimelidine and norzimelidine after intravenous and oral administration of zimelidine

Summary Five healthy adults were administered zimelidine orally (150 mg) and by intravenous infusion (20 mg) in a crossover design. Blood and urine samples were collected for a period of 28 hours after dosing and the concentrations of zimelidine and norzimelidine determined. There was no significant difference in terminal phase half-life of zimelidine after oral (4.7 h±1.3 SD) or intravenous dosing (5.1 h±0.7 SD). An average of 50% of the ingested oral dose reached the systemic circulation. Excretion of unchanged zimelidine in urine was on average 1.26% of the intravenous dose. In appears that zimelidine is completely absorbed from the gastrointestinal tract and first-pass metabolism in the liver reduces the bioavailability to 50%. The mean plasma half-life for norzimelidine was 22.8 h. The area under the plasma concentration time curve for norzimelidine after oral administration was 92% of that after intravenous administration. The plasma concentration of both zimelidine and norzimelidine are predicted to approach steady-state within 3–5 days.     

Involvement of catecholamines and serotonin in human hypertension

Lumber cerebrospinal fluid (CSF) concentrations of metabolites of noradrenaline, adrenaline and serotonin were estimated in patients of sustained hypertension (n = 20), and healthy controls (n = 15). Platelet uptake of serotonin and its basal contents were also estimated in the same individuals. CSF 5-hydroxy indole acetic acid level (5-HIAA) (major metabolite of serotonin) was significantly higher in hypertensives than controls (p less than .01). CSF 3-methoxy, 5-hydroxy phenyl glycol (MHPG) (major metabolite of adrenaline and noradrenaline) level was also raised significantly in cases of hypertension (p less than .01). However, platelet uptake of serotonin as well as its basal contents in hypertension were significantly lower than controls (p less than .01). It can thus be postulated that there exists an increased central serotonergic and catecholaminergic activity in hypertension. Furthermore, alterations observed in platelet serotonin uptake and its basal content suggest the involvement of platelet serotonergic system in hypertension.     

Pharmacokinetic study of zimelidine using a new GLC method

A specific, sensitive, rapid and reproducible analytical method for zimelidine [3-(4-bromophenyl)-N,N-dimethyl-3(3-pyridyl)allylamine] and its biologically active demethylated metabolite, norzimelidine, in human plasma was developed using gas-liquid chromatography (GLC) with loxapine as the internal standard. A good separation of zimelidine and norzimelidine was obtained following derivatisation of norzimelidine with heptafluorobutyric anhydride, the retention times being 6.16 and 10.35 minutes, respectively. The sensitivity of the method is 5 ng/ml for zimelidine and norzimelidine. Plasma concentrations of zimelidine and norzimelidine were determined in 10 healthy volunteers following the administration of a single oral dose of 100mg zimelidine. Zimelidine was rapidly absorbed, giving a mean peak plasma concentration of 103.9 +/- 34.8 ng/ml. The mean plasma elimination half-life was 8.4 +/- 2.0 hours for zimelidine and 19.4 +/- 3.6 hours for norzimelidine. After long term administration of zimelidine (100mg bid for the first week, 100mg tid for the second week and 100mg am and 200mg pm for the third and fourth weeks) to 2 depressed patients, plasma concentrations of norzimelidine were 2 to 4 times higher than those of zimelidine.     

Inhibitors of serotonin and noradrenaline uptake in human plasma after withdrawal of zimelidine and clomipramine treatment

Ten patients with endogenous depression, who had not taken any antidepressive drugs for 3 months, were treated with 100 mg b.i.d. zimelidine (five patients) or 75 mg b.i.d. clomipramine (five patients) for 5-10 weeks. Blood samples taken before and at various times after stopping the treatment were analysed for plasma concentrations of the drugs and their desmethylated metabolites, the uptake of 14C-serotonin in platelets incubated in platelet rich plasma, the concentration of serotonin in whole blood, and the inhibitory effect of the plasma on the accumulation of 14C-serotonin and 3H-noradrenaline in rat hypothalamic synaptosomes. It was found that these uptake measures were normalized within 1 to 2 weeks after zimelidine withdrawal, whereas the effects after clomipramine persisted for 3 to 4 weeks. Norzimelidine, the desmethylated metabolite of zimelidine, caused the effects after zimelidine treatment. Both clomipramine and its metabolite desmethylclomipramine were involved in uptake inhibition after clomipramine treatment. The mean pretreatment values of 14C-serotonin uptake in the platelets did not differ significant from an age and sex matched control group.l     

Initial monoamine oxidase-A inhibition by moclobemide does not predict the therapeutic response in patients with major depression A double blind,randomized study

It is generally accepted that the clinical efficacy of monoamine oxidase inhibitors (MAOI) is related to inhibition of this enzyme. In order to evaluate the predictive ability of monoamine oxidase-A inhibition for therapeutic efficacy, the start of treatment effects of moclobemide, a selective, reversible monoamine oxidase-A inhibitor, on plasma concentrations of monoamines and monoamine metabolites were determined. The plasma levels of 3,4-dihydroxyphenylglycol (DHPG, deaminated metabolite of noradrenaline), 5-hydroxyindoleacetic acid (5-HIAA, deaminated metabolite of serotonin), 3,4-dihydroxyphenylacetic acid and homovanillic acid (DOPAC and HVA, deaminated metabolites of dopamine), L-dihydroxyphenylalanine (L-dopa) and noradrenaline were investigated and related to treatment outcome. This was a randomized double blind parallel group study in 47 patients with criteria of major depression according to DSM III R. Moclobemide 300 mg/day, 450 mg/day or 600 mg/day was administered continuously for 6 weeks. Plasma concentrations of monoamine metabolites and monoamines were determined just before treatment by moclobemide, 4 h after the first dose, 24 h after the first dose, before the first dose on day 7, and 4 h after the first dose on day 7. Each moclobemide dose improved depression as measured by MADRS (Montgomery-Asberg Depression Rating scale) but there was no difference between the three doses. Moclobemide dose-dependently reduced plasma concentration of DHPG, L-dopa and HVA. No dose-dependent treatment effect was observed for plasma 5-HIAA, noradrenaline and DOPAC. The clinical outcome as defined by the final MADRS score was not related to any start of treatment changes in plasma monoamine metabolites reflecting inhibition of MAO-A. It is concluded that monoamine oxidase-A inhibition at the beginning of the treatment does not predict clinical outcome. Received: 29 February 1996/Final version: 30 May 1996     

Zimelidine: a review of its pharmacological properties and therapeutic efficacy in depressive illness

Zimelidine is a new antidepressant, which is structurally unrelated to the tricyclic and tetracyclic antidepressants. The pharmacological profile of zimelidine is different to that of other antidepressants in that it appears to owe the major part of its activity to the inhibition of serotonin uptake within the central nervous system. It appears that the demethylated metabolite, norzimelidine, may be responsible for most of the pharmacological activity. Studies to date suggest that zimelidine has overall efficacy comparable with that of amitriptyline, desipramine, maprotiline and doxepin in depressive illness, but at dosages which have achieved a similar overall clinical improvement zimelidine does not cause sedation, and anticholinergic side effects are mild and occur infrequently. Preliminary evidence suggests that zimelidine is effective against concomitant anxiety in depressed patients, and that it may also be useful in treating phobic anxiety. Zimelidine appears less likely to cause serious cardiotoxicity, in therapeutic dosages or an overdosage, than the tricyclic antidepressants, but it has not been studied in patients with cardiovascular disease. Sleep disturbance has occurred significantly more frequently during zimelidine therapy than during therapy with other sedative antidepressants, but whether this simply reflects the absence of sedation with zimelidine, or an effect on sleep as such, is presently unclear. Zimelidine appears to be effective and well tolerated in elderly patients. Thus, some aspects of the drug's profile (e.g. apparent low incidence of anticholinergic effects or drowsiness) may offer potential advantages in some patients; however, clinical experience with zimelidine to date has been limited, and further well designed studies are required to define the role of the drug more clearly in treating depressive illness compared with other antidepressants, and particularly to define whether some types of depression may respond more readily to zimelidine than to other antidepressants.     

Effects of 2,4,5-trichlorophenoxyacetic acid and quinolinic acid on 5-hydroxy-3-indoleacetic acid transport by the rabbit choroid plexus: Pharmacology and electron microscopic cytochemistry

2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) reduced the uptake of 5-hydroxy-3-indoleacetic acid (5-HIAA) by the choroid plexus in a dose-related manner, while treatment with quinolinic acid at comparable concentrations did not inhibit 5-HIAA uptake. The role of carrier-mediated transport in the clearance of 5-HIAA from cerebrospinal fluid (CSF) was also evaluated in vivo by ventriculocisternal perfusion. Steady-state clearance of 5-HIAA from CSF exceeded that of inulin and was reduced competitively in the presence of 2,4,5-T. However, the clearance was not affected by quinolinic acid. The effect of 2,4,5-T on transport enzyme systems was also studied by electron microscopic cytochemistry. Na+-K+-ATPase and cytochrome oxidase activities in the choroid plexus were reduced by 2,4,5-T. Since this transport system in the choroid plexus is normally responsible for the excretion of the serotonin metabolite from the brain to the plasma, accumulation of endogenously produced organic acids in the CSF and the brain, secondary to reduced clearance by the choroid plexus, could be a contributing factor in the development of neurotoxicity.     

Acute changes in cerebrospinal fluid 5-HIAA following oral paroxetine challenge in healthy humans.

A number of studies have reported decreased human lumbar cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), following chronic administration of selective serotonin reuptake inhibitors (SSRIs). This decrease has been thought to be a consequence of elevated extracellular serotonin and to be mediated through terminal autoreceptor feedback inhibition of serotonin turnover. We wished to study the previously unexamined acute effects of SSRI administration on human CSF 5-HIAA. A serial lumbar puncture (LP) procedure was used to collect CSF samples before and after a single oral 40 mg dose of the SSRI paroxetine (PAR) or matching placebo in eight healthy adult humans in a randomized, double-blind fashion. CSF 5-HIAA concentrations did not change following placebo, but showed a statistically significant 27% mean increase 3 h following PAR. Our findings stand in contrast to the decreases reported for CSF 5-HIAA after chronic SSRI treatment in humans and the decreases seen in brain extracellular 5-HIAA after acute or chronic administration of SSRIs to animals.     

Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers

The dystrobrevin binding protein-1 (DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects (n = 132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers.     

Plasma levels of maprotiline and zimelidine and their relationship to clinical response in depressed patients

Plasma levels of maprotiline, zimelidine, and their respective demethylated metabolites were analyzed, and their relationship to the clinical response was examined, in 60 depressed patients given the drug treatment for 4 weeks. Significant correlation was found between zimelidine and norzimelidine levels (r = 0.531; p less than 0.05) as well as between the steady-state levels of total zimelidine and concentration of the drug 12 h after a single dose (r = 0.753; p less than 0.001). The ratios of drugs and their metabolites in individual patients remained remarkably constant throughout the study. Significant correlations between Hamilton Depression Rating Scale (HAMD) scores and plasma levels of total maprotiline (r = 0.613; p less than 0.05) or norzimelidine (r = -0.552; p less than 0.05) were observed in subgroups of retarded depressives on day 14, and between HAMD scores and norzimelidine levels in retarded depressives (r = 0.703; p less than 0.02) and all patients (r = 0.436; p less than 0.02) on day 28. Both maprotiline and zimelidine produced marked decreases in mean HAMD scores by the end of treatment, but the overall clinical response between the various subgroups was not significantly different (x2 = 3.15; df = 3). Responders and nonresponders to treatment could not be distinguished by mean plasma levels of drugs or their metabolites when all patients were considered. However, a significant difference was found in maprotiline levels between responders and nonresponders within a subgroup of retarded depressives.     

Effect of the antiepileptic di-n-propylacetamide on 5-hydroxytryptamine turnover in the brain and 5-hydroxyindoleacetic acid level in the cerebrospinal fluid

The effect of antiepileptic drug di-n-propylacetamide (DPM) on 5-hydroxytryptamine (5-HT) turnover in rat brain and 5-hydroxyindoleacetic acid (5-HIAA) in cat cerebrospinal fluid (CSF) was investigated. DPM (200 mg/kg) increased brain 5-HIAA without altering the 5-HT level. DPM augmented the accumulation of 5-HT induced by monoamine oxidase inhibition with pargyline (80 mg/kg) and enhanced the accumulation of 5-HIAA in the brain following blockade of transport of this metabolite by probenecid (200 mg/kg). Prior inhibition of 5-HT synthesis by p-chlorophenylalanine (300 mg/kg) abolished the DPM-induced increase in cerebral 5-HIAA. DPM (100 mg/kg) given daily for 5 days considerably elevated 5-HIAA in the CSF of cat during the treatment period. We conclude that DPM increases the turnover of 5-HT in brain and that this can be observed by monitoring the 5-HIAA content of CSF.