Amitriptyline efficacy

Trigclic Antidepressants. Imipramine (38) was introduced in the late 1950s as one of the first pharmacotherapies for depression. At that time, chlorproma2ine [50-53-3] was the first effective antipsychotic treatment to be discovered. Researchers looked for similar chemical stmctures and imipramine was found to be effective in the symptomatic treatment of depression. Over the years, other congeners, such as desipramine (39), amitriptyline (40), and dothiepin (41), were synthesized and shown to be clinically efficacious antidepressant dmgs (121). These substances, known under the general mbric of tricycHc antidepressants, share a basic chemical stmcture comprising... 

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricycHc secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricycHc antidepressants marketed in the United States are Hsted in Table 2. 

Thompson C (2001). Amitriptyline still efficacious, but at what cost Br J Psychiatry 178, 99—100. 

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. 

TCAs. Two tricyclics, clomipramine (Anafranil) and amitriptyline (Elavil), have been studied in AN. The obsessive preoccupation with food and body image pathognomonic of AN led clinicians to study clomipramine first, recognizing its well-documented efficacy for the treatment of OCD. Unfortunately, clomipramine did not successfully improve weight gain. Amitriptyline has been evaluated in AN studies with mixed results. 

This group includes compounds with actions on a range of neurotransmitter systems. Their antidepressant efficacy is mediated by reuptake inhibition of serotonin and noradrenaline, although side-effects such as sedation may also be useful. Their use in anxiety disorders is supported by a long history of clinical experience and a reasonable evidence base from controlled trials. Studies support the use of clomipramine (a potent serotonin reuptake inhibitor) in panic disorder and OCD (Lecrubier et al. 1997 Clomipramine Collaborative Study Group 1991), of imipramine in panic disorder and GAD (Cross-National Collaborative Panic Study 1992 Rickels et al. 1993), and of amitriptyline in PTSD (Davidson et al. 1993a). No controlled studies support the use of TCAs in social anxiety disorder. 

Halmi, K.A., Eckert, E.D., Tadu, T, and Cohen, J. (1986) anorexia nervosa treatment efficacy of cyproheptadine and amitriptyline. Arch Gen Psychiatry 43 177-181. 

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). 

Guelfi JD, Pichot P, Dreyfus JF Efficacy of tianeptine in anxious depressed patients results of a multi-center trial versus amitriptyline. Neuropsychobiology 22 41-48, 1989... 

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... 

Based on comparisons with imipramine and amitriptyline, desipramine and nortriptyline (secondary amine compounds) are comparable in efficacy with their tertiary amine parent compounds and clearly superior to placebo (Table 7-5). Clinically, they are often preferred to the tertiary amine compounds because of their less... 

Two studies found maprotiline to be clearly superior to placebo and two other studies found trends in the same direction ( p < 0.001, combined data) (Table 7-5) (105, 106, 107 and 108). More than 1,600 patients were randomly assigned to either maprotiline or a standard HCA 660 on maprotiline did well, and 247 showed minimal improvement, no change, or worsened. For the HCAs (usually imipramine or amitriptyline), 640 patients did well, and 255 showed minimal improvement, no change, or worsened. In summary, 73% did well with maprotiline, and 72% did well with a standard antidepressant. Combining these data with the Mantel-Haenszel test indicated no difference in efficacy (Table 7-6). Maprotiline has a dose-dependent risk of seizures. As with TCAs and amoxapine, overdoses of maprotiline can be lethal. %... 

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 ... 

A double-blind continuation study has been conducted with mirtazapine. As with venlafaxine and nefazodone, patients in this acute, double-blind, placebo- and active-controlled study with mirtazapine could remain on the double-blind treatment at the end of the initial 6-week efficacy trial and were then followed up for up to 1 year. There was a statistically significant lower risk of relapse (defined as HDRS > 16) on both mirtazapine (18%) and amitriptyline (28%) in comparison with placebo (53%), indicating that mirtazapine has maintenance efficacy (274). More recently, a 40-week, double-blind, placebo-controlled crossover study was performed with mirtazapine (275). Patients maintained on this drug had less than half the likelihood of relapsing than those patients switched to placebo (i.e., 19.7% versus 43.8%, p <0.01). 

The results for this tertiary amine tricyclic are less convincing in terms of efficacy but quite robust with regard to toxicity. The optimal range for this medication in terms of antidepressant efficacy is approximately 80 to 150 ng/mL (amitriptyline plus nortriptyline). Studies generally found a nonsignificant trend with a remission rate of 48% within versus 29% outside this range. 

Zivkov M, Roes KCB, Pols AB. Efficacy of Org 3770 (mirtazapine) vs. amitriptyline in patients with major depressive disorder a meta-analysis. Hum Psychopharmacol 1995 10 S135-S145. 

Sedative antidepressants, such as amitriptyline, doxepin, or trazodone, in low doses, have hypnotic efficacy and may be less likely to evoke the adverse effects associated with higher doses. 

Kane JM, Lieberman J The efficacy of amoxapine, maprotiline, and trazodone in comparison to imipramine and amitriptyline A review of the literature. Psychopharmacol Bull 1984 20(2) 240. [PMID 6374720]... 

The high efficacy of amitriptyline in chronic pain may be in part related to an antagonistic action at NMDA receptors (Eisenach and Gebhart, 1995) (see Table 2). 

Tricyclic antidepressants. Imipramine and clomipramine have been the most extensively studied of the tricyclic antidepressants and both have demonstrated efficacy in treating panic disorder. Other tricyclic antidepressants that have shown some evidence of efficacy include desipramine, doxepin, amitriptyline, and nortriptyline. 

The barbiturates and meprobamate have been entirely superseded by the benzodiazepines and because of their low benefit-to-risk ratio (dependence producing, lethality in overdose, potent sedative effects) they should never be used as anxiolytics. Despite their popularity as short-term sedatives, antihistamines are ineffective anxiolytics, while the use of sedative antidepressants such as amitriptyline should be limited to the treatment of patients with symptoms of both anxiety and depression due to their limited efficacy and the poor patient compliance associated with their adverse effects. However, patients with panic disorder do appear to show a beneficial response to antidepressants (see Chapter 6). A similar argument... 

Spurred on by Laughren s (1991) critique, an exchange of memos occurred between Paul Leber and his boss, Robert Temple, Director, Office of Drug Evaluation 1. The continuing subject was the approval of Zoloft, whose efficacy as an antidepressant remained in doubt up to the last minute. Temple noted that Zoloft was not being approved in some European countries because of its lack of robustness in the efficacy trials. Zoloft often failed to do any better than placebo in studies in the United States and never did as well as the older antidepressant amitriptyline. Despite these pervasive failures, one positive study and two supportive studies were found sufficient to earn approval. 

In a major review of amoxapine and its pharmacology it was concluded that it is similar in efficacy and potency to standard tricyclic compounds, with a sedative action intermediate between amitriptyline and imi-pramine (1). 

Amoxapine is less potent than other tricyclic antidepressants, with a therapeutic dosage range of 75-600 mg/day (usually 200-400 mg/day). Clinical effects have not been consistently correlated with plasma concentrations, but amoxapine has similar efficacy to other tricyclic antidepressants in heterogeneous populations of depressed patients. Controlled comparisons have shown that its clinical profile is very similar to that of imipra-mine (3) and that it is somewhat less sedative than amitriptyline (4-6). In two of these studies (4,6) the... 

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