Imipramine specificity

Older- tricyclic antidepressants are set in italics. The specificity of action of tricyclic antidepressants (in particular of amitritpyline, imipramine, doxepine, nortriptyline, duloxetine, maprotiline) is limited because at therapeutic levels these drugs also block recqDtors (Hrhistamine, aradrenergic, muscarinic). 

Pankey et al.21 described a rapid, reliable, and specific enzyme multiplied immunoassay technique (EMIT ) for amitriptyline, nortriptyline, imipramine, and desipramine in sera. To overcome crossreactivity, solid phase extraction was included in sample pretreatment. Disposable 1 mL columns packed with covalently labeled silica gel were conditioned with HPLC-grade methanol (1 mL) and then with de-ionized or distilled water (1 mL). Serum (calibrator, control, or patient sample, 500 L) was applied onto the column, eluted to waste, washed with 900 /uL of wash solution containing acetonitrile (236.1 g/L) and ion-pairing reagent in acetate buffer, pH 4.2, washed with 500 fiL of mobile phase solution containing acetonitrile (393.5 g/L) in methanolic phosphate buffer, pH 7.0,... 

This conclusion is supported by the mechaiusm of action of imipramine. Once a neurotransmitter has been released into the synapse, there are two ways to terminate its action. The first is to degrade it to inactive products, by MAO for example. The second is to remove the neurotransmitter through reuptake into the presynaptic neuron. This mechaiusm is the predominant one for clearing the synapse of serotonin, norepinephrine, and dopamine. Specific proteins embedded in the neuronal plasma membrane mediate the reuptake of these monoamine neurotransmitters. Imipramine is a nonspecific monoamine reuptake inhibitor that is, it slows the reuptake of aU three of these monoamines, which enhances the activity of these neurotransmitters. This also suggests that a deficit in the activity of one or more of the monoamines underlies the problem of depression. 

A breakthrough in the treatment of major depression was the discovery of fluoxetine, marketed as Prozac. Fluoxetine has a mechanism of action similar to that of imipramine with an important exception. It is a selective serotonin reuptake inhibitor, an SSRI. This strongly suggests that, in some sense, the symptoms of major depression result from a deficit in serotonin specifically. By inhibiting its reuptake from the synapse, the activity of serotonin is enhanced. Two other important drugs for major depression, sertraline (Zoloft) and paroxetine (Paxil), among several others,... 

Many antidepressant drugs have pronounced effects on sleep. Several tricyclic compounds (amitriptyline and others) have sedative actions while others (imipramine and others) are less sedative or even stimulant. Monoamine oxidase inhibitors (MAOIs) have central stimulant effects and may cause insomnia. Specific serotonin reuptake inhibitors (SSRls) and combined serotonin, noradrenaline reuptake inhibitors (SNRIs) can also cause insomnia. 

This chapter describes the structure and neurochemical function of TCAs, metabolism and significant interactions with other medications, side effects, and specific recommendations for monitoring of side effects in children and adolescents. Because of the recent concern regarding the sudden deaths of children stabilized on TCAs, particular attention will be paid to the potential cardiovascular effects of these medications. The chapter will focus on the five TCA medications that have been most widely used in children amitriptyline (AMI), nortriptyline (NT), imipramine (IMI), desipratnine (DMI), and clomipramine (CMI). 

Tanger, S.Z., Javoy-Agid, E, Raisman, R., Briley, M., and Agid, Y. (1981) Distribution of specific high-affinity binding sites for [3H]imipramine in human brain./ Neurochem 37 267—271. 

In recent years the psychostimulant male/female ratio appears to have narrowed to 1 6, in contrast to the 1 12 ratio in the mid-1980s (Safer, 1994). Similarly, Zito et al. (2000) noted that the male/female ratio for prescription frequency has also narrowed among preschoolers in two of three data sets (roughly 4-7 1 to 3-4 1). One interesting exception to this general male female ratio has been noted, however. Zito et al. (1998b) report that for children under the age of 15 years, males are more likely to receive psychotropic treatments (specifically methylphenidate, desipramine, and imipramine) than females. But in youth ages 15 years and older, females received the majority of psychotropic prescriptions. 

After long-term administration, antidepressants may enhance dopaminergic neurotransmission, even if direct acute effects are absent (Serra et al. 1990b). For example, the stress-induced decrease in the binding of quinpirole, an agonist of Dj and Dj receptors, can be reversed by chronic imipramine treatment [Papp et al. 1994). These and related data, however, do not allow the formulation of a dopamine hypothesis of depression, but rather point to a role for decreased dopaminergic neurotransmission in specific neuronal circuits that are responsible for those depressive syndromes associated with motivational loss, psychomotor retardation, and anhedonia [Willner 1995). 

Precursor therapy as a means of increasing dopaminergic transmissions is limited to L-tyrosine and L-dopa. Although under basal conditions the exogenous administration of tyrosine leads to specific enhancement of noradrenergic transmission, it can enhance dopaminergic transmission in conditions of DA deficiency [Kapur and Mann 1992). Only one adequately controlled clinical trial has been reported, in which 65 patients with major depression were randomly selected to treatment for 4 weeks with oral L-tyrosine 100 mg/kg/day, imipramine 2.5 mg/kg/day, or placebo [Gelenberg et al. 1990). Tyrosine increased and imipramine decreased excretion of the main metabolite of NA, but no evidence was found that tyrosine had antidepressant activity in contrast with imipramine. 

Although postsynaptic DA agonists and presynaptic Dj autoreceptor antagonists share a common property of enhancing DA transmission, Dj autoreceptor agonists have been developed specifically to block DA transmission as an alternative approach to antipsychotic therapy (Benkert et al. 1992). A variety of such compounds are available (Seyfried and Boettcher 1990), four of which—talipexole, pramipexole, roxindole, and OPC-4392 —have been evaluated as antipsychotics in schizophrenic patients (Benkert et al. 1992). Only roxindole has been tested in depression, and then only in two uncontrolled pilot studies over 4 weeks of treatment (Benkert et al. 1992 M. Kellner et al. 1994). Response rates similar to those of imipramine were observed, with a fast onset of action in some patients. Roxindole s antidepressant action may lie in its ability to selectively stimulate supersensitive postsynaptic Dj receptors, and thereby enhance DA function, or in its additional properties as an inhibitor of serotonin reuptake and as a 5-HT, receptor agonist (Benkert et al. 1992 Seyfried et al. 1989). 

D PP, Tam YK, Young LT, et al Dthium decreases Gs, Gi-1 and Gi-2 alpha-subunit mRNA levels in rat cortex. Eur J Pharmacol 206 165-166, 1991 Debhch I, Yirmiya R Naltrexone reverses a long term depressive effect of a toxic lithium injection on saccharin preference. Physiol Behav 39 547-550, 1987 DebowitzMR Social phobia. Mod Probl Pharmacopsychiatry 22 141-173, 1987 Debowitz MR, Quitkin EM, Stewart JW, et al Phenelzine vs. imipramine in atypical depression a preliminary report. Arch Gen Psychiatry 41 669-677, 1984 liebowitz MR, Quitkin EM, Stewart JW, et al Antidepressant specificity in atypical depression. Arch Gen Psychiatry 45 129-137, 1988 Liebowitz MR, Schneier F, Campeas R, et al Phenelzine vs atenolol in social phobia. Arch Gen Psychiatry 49 290-300, 1992... 

After the discovery of drugs with antidepressant activity in the late 1950s, an intensive search was undertaken for pharmacological models that would provide an understanding of the therapeutic effects observed and at the same time assist in the development of other, still more effective and specific antidepressants. In pharmacological tests then available, the prototype imipramine showed sedative, antihistaminic and anticholinergic effects and thus did not differ fundamentally from other medicaments with no antidepressant activity, e.g. antihistamines. The following observations then led to a further step forward in the development of hypotheses ... 

Another approach to correct neurotransmission is to inhibit the reuptake of the neurotransmitters into their presvnaptic endings. If the presynaptic reuptake mechanism of a neurotransmitter is blocked then more of the neurotransmitter will stay in the synaptic cleft and be functionally available. Many antidepressant drugs, called reuptake inhibitors , are thought to act via this mechanism. If selective for serotonin they are called selective serotonin reuptake inhibitors (SSRIs, Chapter 1), but if selective for both serotonin and noradrenaline they are called serotonin noradrenaline reuptake inhibitors (SNRIs). Most older antidepressants, such as the tricyclic compounds amitriptyline, imipramine and clomipramine, have little specificity for any of the neurotransmitters fluoxetine, paroxetine, citalopram and a few others are specific for serotonin venlafaxine is a representative of the SNRIs. A more recent mixed-uptake inhibitor is mirtazepine, and some similar compounds are about to be launched. 

A larger set of placebo-controlled studies show conclusively that imipramine is also effective for the treatment of panic disorders. Other agents shown to be effective in panic disorders include the SSRIs paroxetine, sertraline, fluvoxamine, fluoxetine and citalopram. Generally, initial treatment of moderate to severe panic disorders may require the initiation of a short course of benzodiazepines e.g. clonazepam (0.5 1 mg twice daily), and an SSRI. The patient will obtain immediate relief from panic attacks with the benzodiazepine whereas the SSRI may take 1 6 weeks to become effective. Once a patient is relieved of initial panic attacks, clonazepam should be tapered and discontinued over several weeks and SSRI therapy continued thereafter. There are no pharmacological treatments available for specific phobias, however controlled trials have shown efficacy for several agents, e.g. phenelzine, moclobemide. clonazepam, alprazolam, fluvoxamine. sertraline and paroxetine in the treatment of social phobia (Roy-Byrne and Cowlev, 2002). 

Overall JE, Hollister LE, Meyer F, et al. Imipramine and thioridazine in depressed and schizophrenic patients. Are there specific antidepressant drugs JAMA 1964 189 605-608. 

Schou M. Normothymotics, mood normalizers are lithium and the imipramine drugs specific for affective disorders ... 

Although several studies have found that the combination of imipramine and behavioral therapy may be superior to either treatment alone, no studies have specifically examined the effects of combining the behavioral techniques with BZDs (132, 133,134, 135,136, 137 and 138). In a review of the literature, however, Wardle found that diazepam was superior to placebo in three of four studies in which patients also received exposure therapy ( 139). Combined treatment with BZDs and CBT may be advantageous for some patients, but it must be carefully designed to avoid potential problems ( 140). 

Although the term pseudoneurotic schizophrenia has been dropped from the nomenclature, Klein ( 219) made an interesting observation regarding the drug treatment of this condition. Specifically, in an investigation comparing the effects of chlorpromazine and imipramine in a wide variety of patients, imipramine was observed to be beneficial. Thus, in this controlled study, imipramine produced a positive outcome in 60% of subjects, in contrast to placebo, which produced only a 25% positive outcome. 

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking 04 receptors, but the mechanism remains unclear. 

NE molecules released into the synaptic space are reabsorbed back into the presynaptic neuron by the membrane NE transporter (NET). This process requires ATP. The NET is a target for numerous drugs. Several tricyclic antidepressants (TCA), such as imipramine, non-specifically inhibit both NET and 5-HT (5-HTT) transporters (Corrodi and Fuxe 1968). Other TCAs, called norepinephrine reuptake inhibitors (NRIs), such as desipramine, specifically inhibit the NET (Curet et al., 1992 Lacroix et al., 1991). There are also non-tricyclic selective inhibitors of the NET, called selective norepinephrine reuptake inhibitors (SNeRIs), and dual inhibitors of the NET and 5-HTT (SNRIs). The examples for SneRIs and SNRIs are reboxetine and venlafaxine, respectively (Beique et al., 1998a Beique et al., 1998b Beique et al., 1999 Dawson et al., 1999 Szabo and Blier 2001c). 

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