Imipramine Norepinephrine

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

The tricyclic antidepressants (TCAs), such as imipramine, can alleviate symptoms of ADHD. Like bupropion, TCAs likely will improve symptoms associated with comorbid anxiety and depression. The mechanism of action of TCAs is in blocking norepinephrine transporters, thus increasing norepinephrine concentrations in the synapse the increase in norepinephrine is believed to alleviate the symptoms of ADHD. TCAs have been demonstrated to be an effective non-stimulant option for ADHD but less effective than stimulants. However, their use in ADHD has declined owing to case reports of sudden death and anticholinergic side effects6,13 (Table 39-3). Further, TCAs may lower seizure threshold and increase the risk of car-diotoxicity, (e.g., arrythmias). Patients starting on TCAs should have a baseline and routine electrocardiograms. 

Iproniazid and imipramine seemed to work as antidepressants, but how did they achieve their effects It would be another decade before the chemical-imbalance theory was launched. In 1965, Joseph Schildkraut at the National Institute of Mental Health in Washington, DC, published a groundbreaking paper in which he argued that depression was caused by a deficiency of the neurotransmitter norepinephrine in the gaps between neurons in the brain.8 Two years later Alec Coppen, a physician at West Park Hospital in Surrey, published another version of the chemical-imbalance theory. His version differed from Schildkraut s in that it put most of the blame on a different neurotransmitter, emphasizing serotonin rather than norepinephrine as the neurotransmitter that was lacking.9... 

The answer is that there are two ways in which neurotransmitter levels might be increased. One is to inhibit their destruction after they have been released into the synaptic gap. That is how MAOIs are supposed to work. Recall, however, that after a neurotransmitter is released, some of its molecules are reabsorbed by the presynaptic neuron that released them in a process that is called reuptake . Blocking this reuptake process should also increase the level of neuro transmitters in the brain. In 1961, Julius Axelrod, who later received the Nobel Prize in Medicine for his work on the release and reuptake of neurotransmitters, reported that imipramine, as well as a few other drugs, inhibited the reuptake of norepinephrine in cats. Two years later he reported that these drugs also inhibited the reuptake of serotonin.13... 

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

Antidepressant Some animal models show antidepressant effects of lobelia extract (Subarnas et al. 1992). Similar to imipramine and mianserin, beta-amyrin palmitate shows antidepressant-like effects in the forced-swimming test (Subarnas et al. 1993a). Whereas mianserin and beta-amyrin palmitate reduce locomotor activity induced by methamphetamine, imipramine increases it. It potentiates sodium pentobarbital-induced sleep more potently than imipramine, but less than mianserin. Collectively, the effects of beta-amyrin palmitate in behavioral and physiological assays suggests it may work in a manner more similar to mianserin than imipramine. However, the mechanism of antidepressant-like effects of lobelia is uncertain. It may be through the beta-amyrin palmitate s ability to release norepinephrine (Subarnas et al. 1993b). An antidepressant effect of lobelia has not been established in humans. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

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. 

Tricyclic Antidepressants (TCAs). The TCAs have been nsed to treat ADHD for 30 or more years. Most often used are imipramine (Tofranil) and desipramine (Norpramin), mainly becanse they are the TCAs that most specihcally increase norepinephrine activity. Remember, boosting norepinephrine activity in the brain shonld improve attention. Other TCAs, namely, amitriptyline (Elavil, Endep) and nortriptyline (Pamelor), have been used, though they also increase norepinephrine activity. TCAs do offer a modest benefit for both the inattention and the hyperactivity of ADHD. In addition, they are often effective at doses mnch lower than those required to treat depression. However, their effectiveness nsnally falls short of the stimulant medications. In addition, TCAs have considerable side effects including dry mouth, constipation, drowsiness, weight gain, and adverse cardiac effects. 

Imipramine (Tofranil) [Antidepressant/TCA] WARNING Close observation for suicidal thinking or unusual changes in behavior Uses Depres-sion, enuresis, panic attack, chronic pain Action TCA t CNS synaptic serotonin or norepinephrine Dose Adults. Hospitalized Initial 100 mg/24 h PO in doses T over several wk 300 mg/d max Output Maint 50-150 mg PO hs, 300 mg/24 h max Peds. Antidepressant 1.5-5 mg/kg/24 h daUy-qid Enuresis >6 y 10-25 mg PO qhs T by 10-25 mg at 1-2-wk int vals (max 50 mg for 6-12 y, 75 mg for >12 y) Rx for 2-3 mo, then tap Caution [D, /-] Contra Use w/ MAOIs, NAG, acute recovery from MI, PRG, CHF, angina, CVD, arrhythmias Disp Tabs, caps SE CV Sxs, dizziness, xerostomia, discolored urine Interactions t Effects W/ amiodarone, anticholinergics, BBs, cimetidine, diltiazem, Li, OCPs, quinidine, phenothiazines, ritonavir, verapamil, EtOH, evening primrose oil t effects OF CNS depressants, hypoglycemics, warfarin T risk of serotonin synd W/MAOIs 4-... 

Nalepa I, Kreiner G, Kowalska M, Sanak M, Zelek-Molik A, Vetulani J (2002) Repeated imipramine electroconvulsive shock increase alpha(lA)-adrenoceptor mRNA level in rat prefrontal cortex. Eur J Clin Pharmacol 444 151-159 Nesse RM, Ciu-tis GC, Thyer BA, McCann DS, Huber-Smith MJ, Knopf RF (1985) Endocrine and cardiovascular responses during phobic anxiety. Psychosom Med 47 320-332 Nisenbaiun LK, Zigmund MJ, Sved AF, Abercrombie ED (1991) Prior exposure to chronic stress results in enhanced synthesis and release of hippocampal norepinephrine in response to a novel stressor. J Neurosci 11 1473-1484 Nutt DJ (1989) Altered alpha2-adrenoceptor sensitivity in panic disorder. Arch Gen Psychiatry 46 165-169... 

Imipramine is a TCA with mixed serotonin and norepinephrine properties. Sertraline belongs to the class of antidepressants know as the SSRIs and selectively blocks neuronal reuptake of serotonin. 

Imipramine Tertiary Blockade of norepinephrine reuptake at 0.2 autoreceptor and blockade of serotonin reuptake at 5-HTi autoreceptor 13 2 42 2 Enuresis, age 6+ years... 

Venlafaxine, paroxetine, sertraline, imipramine, and trazodone have all proven effective in relieving symptoms of GAD. Venlafaxine, a combined serotonin and norepinephrine reuptake blocker, may be an exceptionally good choice for people who have other psychiatric illnesses in addition to GAD, or when it is not clear whether the patient has GAD or a depressive illness, or both. Although, to date, only certain SSRIs have been... 

Pohl RB, Wolkow RM, Clary CM Sertraline in the treatment of panic disorder a double-bhnd multicenter trial. Am J Psychiatry 155 1189-1195, 1998 Poirer MF, Galzin AM, et al Short-term hthium administration to healthy volunteers produces long-lasting pronounced changes in platelet serotonin uptake but not imipramine binding. Psychopharmacology 94 521-526, 1988 Poiiier-littre MF, Loo FI, Dennis T, et al Dthium treatment increases norepinephrine turnover in the plasma of healthy subjects (letter). Arch Gen Psychiatry 50 72-73, 1993... 

Swann AC Norepinephrine and (Na, K )-ATPase evidence for stabilization by lithium or imipramine. Neuropharmacology 27 261-267, 1988... 

S. Z. Danger, C. Moret, R. Raisman, M. D. Dubocovich, M. Briley (1980). High-affinity H-imipramine binding in rat hypothalamus association with uptake of serotonin but not norepinephrine. Science 210 1133-1135. 

It is thus understandable why some earlier authors previously doubted the efficacy of antidepressants in general (Weiner et al.. 1980) or the advantages of newer antidepressants compared with classical products (Song et al., 1993). However, the great majority of doctors and scientific authors consider that the efficacy of first-generation antidepressants (imipramine, amitriptyline, nortriptyline) has been proved beyond any reasonable doubt, and that efficacy also has been demonstrated for newer products such as trazodone, the selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake... 

Once the antidepressant effect of imipramine had been recognized, a large number of imipramine-like compounds with no really novel features were developed and marketed (Chapter 1). According to the Swedish pharmacologist Arvid Carlsson (1998), the next step occurred as follows "During the 1960s the mechanism of action of imipramine was generally believed to be a blockade of norepinephrine reuptake. However, late in the same decade this... 

This was put forward in 1965 by J. Schildkraut and states that some, if not all, depressions are the consequence of an absolute or relative deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain (Schildkraut, 1965, p. 509). The evidence brought forward in support of this hypothesis was impressive (Table 4.2) because it covered both clinical and multifarious pharmacological findings. The antidepressant effect of imipramine and of the monoamine oxidase (MAO) inhibitors was attributed to the fact that these medicaments bring about an increased supply of functionally available catecholamines at the synapse ... 

Lake CR, Mikkelsen EJ, Rapoport JL. Effect of imipramine on norepinephrine and blood pressure in enuretic boys. Clin Pharmacol Ther 1979 39 647-647. 

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. 

SNRIs are chemically unrelated to each other. Venlafaxine was discovered in the process of evaluating chemicals that inhibit binding of imipramine. Venlafaxine s in vivo effects are similar to those of imipramine but with a more favorable adverse-effect profile. All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters, as do the TCAs. However, unlike the TCAs, the SNRIs do not have much affinity for other receptors. Venlafaxine and desvenlafaxine are bicyclic compounds, whereas duloxetine is a three-ring structure unrelated to the TCAs. Milnacipran contains a cyclopropane ring and is provided as a racemic mixture. 

The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effects initially, its metabolite, desipramine, then balances this effect with more NET inhibition. 

The action of norepinephrine is terminated by reuptake mechanisms, two of which have been identified. Biogenic amine Uptake 1 is located in the presynaptic membrane, requires energy for the transport, is sodium and temperature dependent, and is inhibited by ouabain (a cardiac glycoside), cocaine (a local anesthetic), and imipramine (an antidepressant). Biogenic amine Uptake 2 is located extraneuronally in various smooth muscles and glands, requires energy, and is temperature dependent. Approximately 20% of the amine is either taken up by the Uptake 2 mechanism or is metabolized. 

Tricyclic antidepressants—so called because of the characteristic three-ring nucleus—have been used clinically for four decades (Figure 30-1). They closely resemble the phenothiazines chemically and, to a lesser extent, pharmacologically. Like the latter drugs, they were first thought to be useful as antihistamines with sedative properties and later as antipsychotics. The discovery of their antidepressant properties was a fortuitous clinical observation. Imipramine and amitriptyline are the prototypical drugs of the class as mixed norepinephrine and serotonin uptake inhibitors though they also have several other properties. 

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). 

Reuptake Norepinephrine transporter Tricyclic antidepressants (imipramine, f) Tricyclic norepinephrine reuptake inhibitors (desipiamine, ) Selective norepinephrine reuptake inhibitors (reboxetine, ) Dual serotonin/ norepinephrine reuptake inhibitors (venlafaxine, J.)... 

Differential scanning calorimetry has also been used to study the interaction of DPPC liposomes with the neuromediators norepinephrine and 5-hydroxytryptamine and four antidepressant drugs (imipramine, indalpine, citalopram, and milnacipran) known to inhibit uptake of these neurotransmitters [39]. Changes in the thermograms, transition temperature maximum, Tt, and ATt were determined as a function... 

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