Fluoxetine Amitriptyline

Allen D, Lader M, Curran HV, A comparative study of the interactions of alcohol with amitriptyline, fluoxetine and placebo in normal subjects. ProgNeuropsychopharmacolBiolPsy-chiatry 12, 63-80,... 

Bertschy G, Vandel S, Perault MC. Un cas d interaction metabolique amitriptyline, fluoxetine, antituberculeux. Therapie (1994) 49, 509-12. 

Casamenti et al. [1399] developed a method for screening 11 central nervous system drugs (phenobarbital, olanzapine, clozapine, risperidone, loxapine, haloperidol, imipramine, amitriptyline, fluoxetine, chlorpromazine, paroxetine) on a Cjg column (A = 230 nm) using a 20/11.7 water (0.4g tetramethylammonium perchlorate with 0.2 mL of 7% (m/m) HCIO4 to pH 2.8 with ammonia)/acetonitrile mobile phase. Keep in mind that perchlorates, when concentrated with some metals, are hazardous. Elution was complete in 35 min with good resolution for most compounds. Plots of the effects of mobile phase modifier level and percent acetonitrile on overall retention are presented. Linear ranges of 25-5000 ng/mL with detection limits of 10-250 ng/mL (analyte dependent) are reported. 

Two recently introduced antidepressants are notable m that they are selective serotonin uptake inhibitors Citalopram (19) is reported to be as effective as amitriptyline m the treatment of endogenous depression [75, 16] Fluoxetine (20) as the hydrochlonde is approved for major depressive disorders mcludmg those with concomitant anxiety Interestmgly, it also appears useful m the treatment of obesity [17]... 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Decision analytic models have been constmcted to compare the costs of TCAs with those of SSRIs and other compounds. These comparisons have included imipramine or amitriptyline versus paroxetine or sertraline (Stewart, 1994) imipramine versus paroxetine Qonsson and Bebbington, 1994 McFarland, 1994 Lapierre et al, 1995) fluoxetine versus amitriptyline, clomipramine, doxepin and imipramine (Le Pen et al, 1994) venlafaxine versus amitriptyline, desipramine. 

Versiani, M., Ontiveros, A., Mazzotti, G., Ospina, J. et al. (1999). Fluoxetine versus amitriptyline in the treatment of major depression with associated anxiety (anxious depression) a doubleblind comparison. Int. Clin. Psychopharmacol, 14, 321-7. 

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). 

Additional ADRs linked to diet pills include psychosis myocardial ischemia drug interactions, such as the interaction of fenfluramine with imipramine, fenfluramine with amitriptyline or desipramine, or the toxic reaction between fluoxetine and phentermine and the release of serotonin while inhibiting its reuptake, contributing to hyperserotonin reactions. When the next craze takes hold of patients and their physicians, hopefully physicians and pharmacists will take a more vocal position and recommend restraint, xmtil some proof of efficacy and lack of toxicity is shown for new faddish off-label combinations. 

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. 

Solid phase extraction (SPE) has been used to efficiently extract several types of antidepressants, which can then be conveniently analyzed on GC-NPD. One assay extracted and analyzed viloxazine, venlafaxine, imipramine, desipramine, sertraline, and amoxapine from whole blood in one procedure (Martinez et al., 2002). The same laboratory analyzed fluoxetine, amitriptyline, nortriptyline, trimipramine, maprotiUne, clomipramine, and trazodone in whole blood in one assay (Martinez et al., 2003). SPE has also been used for the simultaneous analysis of TCAs and their metabolites by de la Torre et al. (1998). 

Martinez MA, Sanchez de la Torre C, Almarza E. 2003. A comparative solid-phase extraction study for the simultaneous determination of fluoxetine, amitriptyline, nortriptyline, trimipramine, maprotiline, clomipramine, and trazodone in whole blood by capillary gas-liquid chromatography with nitrogen-phosphorus detection. J Anal Toxicol 27 353. 

There are four classes of antidepressants tricyclic antidepressants (imipramine, trimipramine, amitriptyline, doxepin, desipramine, protriptyline, nortriptyline, amoxapine, maprotiline) monoaminooxidase (MAO) inhibitors (phenelzine, isocarboxazid, tranylcypromine) second-generation antidepressants or atypical antidepressants, which are a chemically dissimilar group of recently proposed drugs (bupropion, trazodone, fluoxetine) and amphetamines and other stimulators of the CNS (dextroamphetamine, methylphenidate). 

Clozapine Fluoxetine Amitriptyline Antidepressants Enflurane Antidepressants... 

Sovner et al. (1998) have done an excellent job summarizing the data on antidepressants in patients with developmental disabilities. There have been nine reports of antidepressant use in adults with depression and MR and three reports of antidepressant use in children and adolescents. Eight of nine reports in adults were positive. The drugs studied included nialimide (n = 27), fluoxetine (9), imipramine (6), amoxapine (2), and nortriptyline (1) (total n = 45). In addition, Sovner et al. identified four reports of antidepressant use in children. One involved successful treatment with fluoxetine in an adolescent, another indicated efficacy with imipramine and amitriptyline in 9 of 12 children (Do-sen, 1982), and a third showed successful management in 3 of 4 children treated with imipramine or tryptophan plus nicotinamide (Dosen, 1990). One study of fluoxetine in depressed children with autism and MR witnessed improvement in depression but not in compulsive symptoms (Ghaziuddin and Tsai, 1991). 

CRH binding sites in the frontal cortex of patients with depression who have committed suicide [Nemeroff et al. 1988], the increased number of CRH-expressing neurons in the hypothalamic paraventricular nucleus of patients with depression [Raadsheer et al. 1994], and the finding that CRH concentrations in the spinal fluid decrease during long-term treatment with fluoxetine or amitriptyline [De Beilis et al. 1993] support the idea that CRH is the key neurohormone responsible for HPA alterations in depression. To clarify this point, two questions must be resolved 1] Are all HPA alterations explained by the supposed CRH hypersecretion and 2] Is CRH hypersecretion responsible for the behavioral changes seen in depression ... 

London E, Fanelh RJ, Kimes A, et al Effects of chronic nicotine on cerebral glucose utilization in the rat. Brain Res 520 208-214, 1990 Lonnqvist J, Sihvo S, Syvalahti E, et al Moclobemide and fluoxetine in atypical depression a double-blind trial. J Affect Disord 32 169-177, 1994 Loo H, Malka R, Defance R, et al Tianeptine and amitriptyline controlled double-blind trial in depressed alcoholic patients. Neuropsychobiology 19 79-85, 1988... 

Area of assessment Clinically sedative antidepressants, e.g. amitriptyline, mianserin, trimipramine Less sedative antidepressants, e.g. bupropion, fluoxetin, moclobemide, nefazodone ... 

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. 

Schmider J, von Moltke LL, Shader Rl, et al. Extrapolating in vitro data on drug metabolism to in vivo pharmacokinetics evaluation of the pharmacokinetic interaction between amitriptyline and fluoxetine. Drug Metab Rev 1999 31 545-560. 

Preskorn SH, Baker B. Fatality associated with combined fluoxetine-amitriptyline therapy. JAMA 1997 277 682. 

There have been five double-blind studies comparing the antidepressant efficacy of different SSRIs versus different TCAs in patients with HDRS scores of 25 or more (122, 123,124, 125 and 126). Three of these studies permitted inclusion of both inpatients and outpatients ( 122, 123 and 124), whereas the other two were solely done in outpatients (125, 126). Three were placebo-controlled (1.23, 125,126). In these three studies, the SSRI (i.e., fluvoxamine, paroxetine, or sertraline) was either superior to both the f CA and placebo or was comparable with the TCA and superior to placebo. In the other two studies, the SSRI was not different from the TCA and there was no placebo control. There have also been four studies and one metaanalysis of European clinical trials which found no difference in antidepressant efficacy between several different SSRIs and several different tertiary amine TCAs in patients hospitalized for major depression ( 127,128, 129,130 and 131). Finally, there have been two relatively small studies showing that fluoxetine and fluvoxamine both had antidepressant efficacy superior to placebo in patients with melancholia ( 132, 133). Another larger study failed to find a difference between paroxetine and amitriptyline in treating such patients ( 134). 

The approval of mirtazapine in the United States was based on six double-blind, placebo- and amitriptyline-controlled studies in which it was found to be superior to placebo and comparable with amitriptyline in terms of antidepressant efficacy (173,174). In a double-blind, crossover study, 63% of patients who failed to respond to 6 weeks of double-blind treatment with amitriptyline responded to mirtazapine (175). In two studies, mirtazapine was found to be efficacious in the treatment of patients hospitalized for major depression. In the first study, the antidepressant efficacy of mirtazapine was comparable with that of amitriptyline and superior to placebo (176). In the other study, the antidepressant efficacy was superior to that of fluoxetine (118). There are advantages and disadvantages to mirtazapine, including the following ... 

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