Clinical and biochemical effects during treatment of depression with nortriptyline: The role of 10-hydroxynortriptyline

Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 08/1987; 42(1):10-9. DOI: 10.1038/clpt.1987.101
Source: PubMed


Plasma concentrations of nortriptyline (NT) and its major metabolite 10-hydroxy-NT (10-OH-NT) were measured in 30 patients with depression, treated with NT for 3 weeks. Nine patients who recovered completely had plasma concentrations of NT and 10-OH-NT ranging from 358 to 728 nmol/L and from 428 to 688 nmol/L, respectively. Of the 21 patients who did not recover completely, only four had plasma concentrations within the window limited by these two plasma concentration ranges. A correlation was found between the degree of amelioration and the plasma concentration of NT (rs = 0.469; P less than 0.01). Lumbar punctures were performed in 26 patients before and after 3 weeks of NT treatment. During treatment there was a 30.9% mean decrease in the noradrenaline metabolite 4-hydroxy-3-methoxyphenylglycol (HMPG) in cerebrospinal fluid (CSF). We could not evaluate the extent to which this decrease was caused by NT or 10-OH-NT, respectively, because both are strong inhibitors of noradrenaline uptake. The ratio between the concentration of NT and 10-OH-NT in CSF correlated to the reduction of HMPG in CSF (r = 0.397; P less than 0.05) and to the amelioration of depression (rs = 0.623; P less than 0.001). This might indicate that NT and 10-OH-NT interact on the noradrenaline system in a nonadditive way. During treatment there was a 15.2% decrease in CSF concentration of the serotonin metabolite 5-hydroxyindoleacetic acid. The reduction was significantly correlated to the CSF concentration of NT but not to that of 10-OH-NT. This is in accordance with the fact that NT is a more potent inhibitor of serotonin uptake than is 10-OH-NT. The dopamine metabolite homovanillic acid in CSF decreased significantly by 10.0%. The biochemical data indicate that noradrenergic, serotoninergic, and dopaminergic systems are affected by NT treatment and that 10-OH-NT might be more selective on noradrenergic neurons than the parent drug.

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    • "Preliminary data have been presented at the Third International Meeting on Clinical Pharmacology in Psychiatry in Odense, Denmark, 1982 (Bertilsson et al., 1983) and at the 13th 412 C. Nordin, L. Bertilsson & B. Siwers CINP Congress in Jerusalem, Israel, 1982 (Nordin et al., 1984). "
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    ABSTRACT: After 3 weeks' nortriptyline (NT) treatment the mean plasma concentration of its 10-hydroxy metabolite (10-OH-NT) (599 +/- 207 nmol l-1) was higher than that of the parent drug (433 +/- 199 nmol l-1) in 25 depressed patients. Also in the cerebrospinal fluid (CSF) the mean level of 10-OH-NT (67 +/- 20 nmol l-1) was higher than that of NT (39 +/- 23 nmol l-1). There was a strong correlation (P less than 0.001) between the CSF and plasma concentration of both NT (r = 0.92) and 10-OH-NT (r = 0.77). The interindividual variation in the CSF/plasma ratio of both compounds was small, compared to the variation in plasma levels. These results show that 10-OH-NT passes the blood-brain barrier as it is present in concentrations higher than those of NT in the CSF. 10-OH-NT has previously been shown to be a potent blocker of noradrenaline uptake and to have much less affinity for muscarinic receptors than NT itself. This active metabolite might therefore be a potential antidepressant with less disturbing anticholinergic side-effects.
    British Journal of Clinical Pharmacology 11/1985; 20(4):411-3. DOI:10.1111/j.1365-2125.1985.tb05086.x · 3.88 Impact Factor
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    ABSTRACT: We describe the relationship of 2-hydroxydesipramine (OH-DMI) plasma levels and response in a prospective DMI study in which dosage was rapidly adjusted to achieve a relatively uniform DMI plasma level. In prior studies, OH-DMI plasma levels were not related to response, but in these fixed-dose protocols the effects of OH-DMI are easily obscured by the higher concentrations of the parent drug. We hypothesized that in this study a contribution of OH-DMI to response might become apparent because DMI levels were relatively constant. Inpatients with nonpsychotic, unipolar DSM-III major depression who remained depressed (Hamilton score greater than 18) after 1 week of hospitalization without medication received a 4-week DMI trial. Twenty-four-hour drug plasma levels were used to adjust dose to reach a target DMI steady-state plasma level. Twenty-seven patients completed the trial. On every measure of response, total drug levels (DMI + OH-DMI) were more strongly correlated with outcome than were DMI levels alone. With multiple regression, both DMI and OH-DMI levels were independently and significantly associated with response. These findings suggest that OH-DMI has antidepressant activity.
    Clinical Pharmacology &#38 Therapeutics 10/1988; 44(3):283-8. DOI:10.1038/clpt.1988.151 · 7.90 Impact Factor
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    ABSTRACT: In 28 patients with primary depression, relationships were sought between rating scores on the Montgomery-Asberg Depression Rating Scale and the concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) in cerebrospinal fluid (CSF). Among the single items in the rating scale, reported sadness correlated negatively with HMPG. No other significant relationships were found in the total group of patients. However, in subgroups with low or high concentrations of monoamine metabolites, several significant relationships were found, such as a negative correlation between inner tension and concentration difficulties, respectively, and 5-HIAA in the low-HMPG subgroup. Curvilinear relationships were found between pessimistic thoughts and 5-HIAA in the high-5-HIAA subgroup and between apparent sadness and 5-HIAA in the low-HMPG subgroup. Suicidal thoughts tended to correlate in a curvilinear way with the ratio of HMPG/5-HIAA in the low-HVA and the high-HMPG subgroups, but the curves were mirrored. The results indicate that relationships between clinical symptoms and monoamine metabolite homeostasis in CSF are qualitatively and quantitatively different in defined high-and low-monoamine subgroups of depressed patients.
    Acta Psychiatrica Scandinavica 01/1989; 78(6):720-9. DOI:10.1111/j.1600-0447.1988.tb06411.x · 5.61 Impact Factor
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