Tricyclic antidepressants with fluoxetine

In general, the SSRIs have a more tolerable side effect profile than the tricyclic antidepressants with their anticholinergic effects. Review of the rate that subjects in the controlled studies discontinued a SSRI because of adverse effects provides some perspective on how well tolerated the medications are, although the specifics may vary according to dosage and design (e.g., forced titration) and are not directly comparable. The rate of discontinuation was reported to be 12% (4/48) for fluoxetine (Emslie et ah, 1997), 9.7% for paroxetine (Keller et ah, 2001), 13% (12/92) for sertraline (March et ah, 1998), and 33% (19/57) (Riddle et ah, 2001) and 7.9% (5/63) for fluvoxamine (Walkup et ah, 2001). 

Aranow RB, Hudson JI, Pope HG, et al Elevated antidepressant plasma levels after addition of fluoxetine. Am J Psychiatry 146 911-913,1989 Balick MJ, Cox PA Plants, People, and Culture The Science of Ethno-botany. New York, Scientific American Library, 1996 Barker EL, Blakely RD Identification of a single amino acid, phenylalanine 586, that is responsible for high affinity interactions of tricyclic antidepressants with the human serotonin transporter. Molecular Pharmacology 50(4) 957-965,1996... 

Indalpine is a non-tricyclic antidepressant with a serotonin selective profile. It is 6-7 times more potent than fluoxetine and clomipramine in inhibiting serotonin reuptake m vitro in rat brain synaptosomes. Statistically significant clinical effects within one week of onset of treatment have been reported. An anxiolytic effect may accompany the antidepressant effect. Indalpine appears devoid of anticholinergic and cardiovascular side effects and does not promote weight gain or affect appetite. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

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. 

Duverneuil and coworkers (2003) have developed a method for the determination of 11 of the most commonly prescribed non-tricyclic antidepressants and some of their metabolites these include paroxetine, fluoxetine, norfluoxetine, sertraline, citalopram, fluvoxamine mirtazapine, venlafaxine, and 0-des-methylvenlafaxine. The method involves an LLE procedure followed by an HPLC separation with photodiode-array UV detection at three different wavelengths (220, 240, and 290 nm). The total run time was 18 min. The extraction recoveries were calculated to be in the range of 74-109% and the lower limit of detection (LLOD) reported was 2.5-5 ng/ml. A method published by Tournel and associates (2001) also reported the simultaneous determination of several newer antidepressants by RP-HPLC with UV detection. The compounds were isolated from human serum using an LLE process. The LLOQ ranged from 15-50 ng/ml depending on the analyte of interest. The total run time for all compounds eluted was approximately 20 min. 

Changing a patient from one MAOI to another, or to a TCA, requires a "wash-out" period of at least 2 weeks to avoid the possibility of a drug interaction. There is evidence to suggest that a combination of an MAOI with clomipramine is more likely to produce serious adverse effects than occurs with other TCAs. Regarding the newer non-tricyclic antidepressants, it is recommended that a "wash-out" period of at least 5 weeks be given before a patient on fluoxetine is given an MAOI this is due to the very long half-life of the main fluoxetine metabolite norfluoxetine. 

The efficacy of fluoxetine in treating patients with moderate depression is comparable to the efficacy of tricyclic antidepressants. It is capable of elevating mood and removing feelings of fear and stress. It does not have a sedative effect. Fluoxetine is used in depression as well as in bulemic neuroses. Use of fluoxetine is preferred in cases when sedative, hypotensive, and anticholinergic side effects caused by other antidepressants are con-traindicative to patients. Prozac is a synonym for fluoxetine. 

Tricyclic antidepressants are still prescribed today, but some patients experience side effects such as dry mouth, blurry vision, constipation, and other uncomfortable conditions. Other antidepressants have since been found that induce fewer side effects. One of the most popular is fluoxetine, which is marketed under the trade name Prozac. This drug, along with Zoloft and other antidepressants, are known to inhibit reuptake proteins specifically for serotonin. As a result, these drugs are called selective serotonin reuptake inhibitors, or SSRIs. Although some concerns have appeared because of a possible risk of suicide in young patients who take Prozac, these drugs are commonly prescribed and have proved highly effective in millions of patients. 

In clinical practice, a number of patients with SRI-resistant OCD receive simultaneous treatment with two potent SRls. Apart from encouraging case reports of coadministering fluoxetine and clomipramine in adolescents [Simeon et al. 1990] and adults [Browne et al. 1993] with OCD, the efficacy and safety of this approach have not been subjected to rigorous examination. Because of the risks associated with fluoxetine-induced elevations in plasma levels of tricyclic antidepressants, caution should be exercised when these drugs are used concurrently [Rosenstein et al. 1991]. Clomipramine s potential for lowering seizure threshold is of particular concern, making it advisable to measure clomipramine plasma levels before and after addition of another SRI. 

The clinical and commercial success of the antidepressant compound fluoxetine (Chapter 2 Prozac) engendered considerable work in other laboratories. A benzo-dioxan based compound that shows similar activity shares only a few stmctural features with the prototype. The benzodioxan nucleus (68-3) is formed by an alkylation reaction between the fluorocatechol (68-1) and the derivative (68-2) from meso, and hence achiral, butanetetrol. The benzyl protecting groups are then removed by hydrogenation over palladium, and the thus-obtained diol is converted to the fiii-toluene-sulfonate (68-4) by reaction with toluenesulfonyl chloride. Treatment of that intermediate with benzylamine leads to fiw-alkylation on the same nitrogen to form a pyrrolidine ring and thus the tricyclic compound (68-5). A second hydrogenolysis step then leads to fluparoxan (68-6) [70]. 

A growing number of drugs are used that affect the many neurotransmitters in the brain benzodiazepines and others act on GABAergic transmission antidepressants, such as monoamine oxidase inhibitors and tricyclic antidepressants, are thought to increase the concentration of transmitter amines in the brain and so elevate mood—these will also act at peripheral nerve terminals, so interactions with them are a combination of peripheral and central actions. Levodopa (L-dopa) increases central as well as peripheral dopamine, and the newer class of psychoactive drugs, the selective serotonin reuptake inhibitors (SSRIs) of which the ubiquitous fluoxetine (Prozac) is best known, act in a similar way on serotonergic pathways. 

The depressive phase of manic-depressive disorder often requires concurrent use of an antidepressant drug (see Chapter 30). Tricyclic antidepressant agents have been linked to precipitation of mania, with more rapid cycling of mood swings, although most patients do not show this effect. Selective serotonin reuptake inhibitors are less likely to induce mania but may have limited efficacy. Bupropion has shown some promise but—like tricyclic antidepressants—may induce mania at higher doses. As shown in recent controlled trials, the anticonvulsant lamotrigine is effective for many patients with bipolar depression. For some patients, however, one of the older monoamine oxidase inhibitors may be the antidepressant of choice. Quetiapine and the combination of olanzapine and fluoxetine has been approved for use in bipolar depression. 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

Newer antidepressants (eg, fluoxetine, paroxetine, citalopram, venlafaxine) are mostly SSRIs and are generally safer than the tricyclic antidepressants and monoamine oxidase inhibitors, although they can cause seizures. Bupropion (not an SSRI) has caused seizures even in therapeutic doses. Some antidepressants have been associated with QT prolongation and torsade de pointes arrhythmia. SSRIs may interact with each other or especially with monoamine oxidase inhibitors to cause the serotonin syndrome, characterized by agitation, muscle hyperactivity, and hyperthermia (see Chapter 16). 

Another important CYP450 enzyme for antidepressants is 2D6. Tricyclic antidepressants are substrates for 2D6, which hydroxylates and thereby inactivates them (Fig. 6—14). Several antidepressants from the SSRI class are inhibitors of CYP2D6 (Fig. 6—15). There is a wide range of potency for 2D6 inhibition by the five SSRIs, with paroxetine and fluoxetine the most potent and fluvoxamine, sertraline, and citalopram the least potent. 

When tricyclic antidepressants are given concomitantly with SSRIs such as fluoxetine or paroxetine ... 

Fluoxetine causes weight loss, in contrast to tricyclic antidepressants (417). In one study there was a mean fall in weight of 3.88 pounds over 6 weeks compared with a gain of 4.6 pounds with amitriptyline (418). 

Fluoxetine is a selective serotonin-reuptake inhibitor (SSRI) that produces a net increase in (post-synaptic motor neuron) serotonin delivery after 4-6 weeks of use. A double-blind, randomized cross-over trial compared fluoxetine to the tricyclic antidepressant agent protriptyline and placebo in 12 patients with sleep-disordered breathing [52], The group apnea-hypopnea index (AHI) improved with fluoxetine compared to placebo, but there was great variability of response and other measures of disordered sleep did not change. These potentially beneficial results in a small number of patients need to be replicated in well-designed larger studies to support a useful role in clinical practice. 

Of the tricyclic antidepressants used, clomipramine has been shown to be effective in the treatment of children with obsessional symptoms, effects which have been shown to be independent of the antidepressant action of the drug. More recent studies have provided evidence that the SSRI antidepressants such as fluoxetine are as effective, with fewer side effects. 

Treatment with antidepressants will affect a person s ability to drive or operate machinery. Among the tricyclic antidepressants, amitriptyline and doxepin impair skills compared with imipramine and nortriptyline. Fluoxetine and dothiepin also show similar effects, such as affecting ability to work. The United Kingdom s Medical Commission on Accident Prevention has recommended that patients on long-term psychotropic medication are unsuitable drivers of heavy vehicles or public transport services.132,133... 

Therapeutic uses The primary indication for fluoxetine is depression, where it is as effective as the tricyclic antidepressants. Fluoxetine is effective in treating bulimia nervosa and obsessive-compulsive disorder. The drug has been used for a variety of other indications, including anorexia nervosa, panic disorder, pain associated with diabetic neuropathy, and for premenstrual syndrome. 

The correct answer = B The tricyclic antidepressants and especially imipramine are effective in this condition because it contracts the internal sphincter of the bladder. Fluoxetine and trazodone act at serotonin receptors and have no effect on bladder function. Tranylcypromine is an MAO inhibitor with serious side effects. 

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