Posted by ed_uk on March 6, 2005, at 9:58:40
In reply to Re: My little theory on reboxetine.Therapeutic window?, posted by zeugma on March 5, 2005, at 20:03:57
Hi Z,
>I wonder why nortriptyline has a clear therapeutic window, while its cousin desipramine does not?
Perhaps it does but hasn't been investigated well enough....... or maybe NOT..........
J Clin Psychopharmacol. 1994 Aug;14(4):230-40.Tricyclic antidepressant concentrations in plasma: an estimate of their sensitivity and specificity as a predictor of response.
Perry PJ, Zeilmann C, Arndt S.
Department of Psychiatry, College of Medicine, University of Iowa, Iowa City 52246.
An analysis of the literature on tricyclic antidepressant level in blood using receiver operating characteristics curves as the primary statistical tool was performed. For nortriptyline, a significant curvilinear relationship between therapeutic response and nortriptyline was observed that ranged from 58 to 148 ng/ml. The sensitivity and specificity for the nortriptyline therapeutic window were 78 and 61%, respectively. The response rate within the therapeutic range was 66% versus 26% outside the therapeutic range. For desipramine, a significant linear relationship between therapeutic response and desipramine concentration in plasma was observed. The threshold concentration in plasma for therapeutic response was 116 ng/ml. The sensitivity and specificity for the desipramine threshold level in blood were 81 and 59%, respectively. The response rate above the threshold level was 51% versus 15% below the therapeutic threshold concentration. For imipramine, a significant curvilinear relationship between therapeutic response and total imipramine (imipramine+desipramine) concentration in plasma was observed between 175 and 350 ng/ml. The sensitivity and specificity for the total imipramine concentrations in plasma were 52 and 74%, respectively. The response rate within the therapeutic range was 67% versus 39% outside the therapeutic range. For amitriptyline, a significant curvilinear relationship between therapeutic response and total amitriptyline (amitriptyline+nortriptyline) concentration in plasma was observed between 93 and 140 ng/ml. The sensitivity and specificity for the total imipramine concentrations in plasma were 37 and 80%, respectively. The response rate within the therapeutic range was 50% versus 30% outside the therapeutic range.
Perhaps this has something to do with it......Psychopharmacology (Berl). 1991;104(2):237-43.
Biphasic effect of tricyclic antidepressants on the release of norepinephrine from the adrenergic nerves of the rabbit heart.
Somogyi GT, Perel JM.
Department of Psychiatry, University of Pittsburgh, PA 15213.
The release of norepinephrine (NE) from the right atrium of the rabbit heart was used as a model to investigate biphasic effects due to tricyclic antidepressants, similar to those clinically observed in the treatment of depression and known as "therapeutic window". Strips of the atrium were loaded with 3H-NE, and then superfused by Krebs solution. The basal release and the electrical stimulation evoked release of 3H-NE were measured in the presence and absence of four clinically used tricyclic antidepressants: imipramine, amitriptyline, desipramine and nortriptyline. In addition, guanethidine, an adrenergic neuron blocker, was also studied. At lower concentrations (0.5-10 microM) tricyclic antidepressants increased, whereas higher concentrations (50-100 microM), inhibited the evoked release of NE. This inhibition was not prevented by the alpha2 adrenoceptor antagonist yohimbine, excluding the possibility of alpha 2 adrenoceptor-mediated inhibition of NE release. In higher concentrations the tricyclic antidepressants increased the basal release of NE in a Ca-independent way. Secondary amine derivatives were more potent inhibitors of the evoked release, and enhance the resting basal release of NE to a greater extent than the tertiary ones. Similarly, guanethidine (1-50 microM) also decreased the evoked release and increased the basal release of NE in a concentration dependent manner. Yohimbine failed to counteract the inhibition caused by guanethidine and the increment of the basal release was Ca-independent. *It is concluded that the effect of tricyclic antidepressants in potentiating the release of NE is masked by their adrenergic neuron blocking properties, i.e. they inhibit the release of NE.*
An old report.................Neuropsychobiology. 1982;8(2):73-85.
Tricyclic antidepressant plasma levels: the state of the art and clinical prospects.
Razavi D, Mendlewicz J.
The authors review the main pharmacological factors playing a role in the kinetics of tricyclic antidepressant plasma levels. The current data concerning the relationship between tricyclic plasma levels and their clinical responses indicate that there is a therapeutic window at 50-150 ng/ml for the secondary derivatives (nortriptyline and desipramine). The lower limit of efficiency for the primary derivatives (imipramine and amitriptyline) is estimated at 200 ng/ml. The boundaries and prospects of the clinical use of antidepressant plasma levels are discussed in their various methodological aspects.
Ed.
poster:ed_uk
thread:467005
URL: http://www.dr-bob.org/babble/20050304/msgs/467288.html