Amitriptyline studies/trials

Tricyclic Antidepressants (TCAs). Because of their effectiveness not only for depression but for anxiety disorders such as panic disorder as well, TCAs were the first medications formally tested in the treatment of PTSD. Three TCAs, amitriptyline, imipramine, and desipramine, have been studied in small trials, producing modest benefit for reexperiencing and hyperarousal symptoms, without any relief of avoidance/numbing symptoms. Given this limited benefit in conjunction with the side effect burden and potential for toxicity in a suicide prone population, TCAs are infrequently used in the treatment of PTSD. Please refer to Chapter 3 for more information regarding TCAs. 

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. 

Two later studies attempted to amend some of these deficiencies. One study by W. H. Nelson and colleagues [1984] used a double-blind randomized design to evaluate response in 13 patients with PMD and 12 patients with NPMD who received 150 mg of either imipramine or amitriptyline over a 4-week period. At the end of this trial, 2 of 13 patients with PMD had a Hamilton Rating Scale for Depression [M. Hamilton 1960] score of less than 8 [complete remission of symptoms], whereas 7 of 12 patients with NPMD had achieved remission. 

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). 

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). 

Two placebo-controlled trials found that TCAs were beneficial for PTSD. An 8-week study of amitriptyline (50 to 300 mg per day) versus placebo was conducted in male combat veterans with PTSD. Amitriptyline was found to be more effective than placebo (i.e., a 50% response rate for amitriptyline and a 17% response rate for placebo (270). In another 8-week, placebo-controlled study, imipramine (50 to 300 mg per day) was compared with placebo in 60 Vietnam veterans with PTSD. The results (as indicated by various rating scales) also showed that there was a greater symptom reduction in the imipramine-versus placebo-treated patients ( 271). 

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 systematic review of 32 randomized trials in which 1389 patients took lithium and 2069 took another agent (carbamazepine, divalproex, lamotrigine, or the antidepressants amitriptyline, fluvoxamine, mianserin, and maprotiline), among the seven studies that reported suicides, lithium-treated patients had significantly fewer completed events (242). These included two suicides on lithium (out of 503, 0.4%) and 11 suicides on other agents (two placebo, two amitriptyline, six carbamazepine, and one lamotrigine, out of a total of 601,1.8%) (OR = 0.26 95% Cl = 0.09, 0.77). 

Antidepressants and 5-HT - Because of the possibility of reduced cardlo-toxicity, interest was maintained in 1978 in compounds which are selective inhibitors of 5-HT uptake, many of which were reported in Volume 13 of this series21 and elsewhere. Open clinical studies of zimelldlne ( ) showed good antidepressant effects after doses of 150 mg daily. 7 The claimed rapid onset of action of was not confirmed in the first double-blind trial in hospitalized depressives given single bedtime doses of or amitriptyline for A weeks. 8 No difference in efficacy emerged, but side-effects were fewer with A cardiovascular study showed and mianserin... 

Side-effects of TCA were compared in double-blind trials in healthy subjects. Marked inhibitory effects on salivary flow declined from amitriptyline through doxepin, Imipramine, nortriptyline to desipramine, paralleling subjective reports of anticholinergic side-effects and reported affinities for muscarinic receptors.74 Similar rankings for sedation and decrements in psychometric performance were obtained in another study ... 

A controlled comparator trial of fluoxetine 10 mg/day and amitriptyline 25 mg/day found that both were equally effective however, the fluoxetine group tolerated the medication much better and had significantly lower dropout rates. Similarly, a study com-... 

Traditionally, dysthymic disorder has not been the focus of pharmacotherapeutic interventions, given its chronicity and the presumed non-biological personality variables associated with it. Psychotherapy and psychoanalysis were generally considered the first-choice treatment options, although these treatment modalities have not been well studied in controlled trials. However, as a result of a series of placebo-controlled medical trials, this attitude has been changed. Among the antidepressants found to be superior to placebo are the selective serotonin reuptake inhibitors (SSRIs, with results being evident so far with fluoxetine and sertraline), the tricyclic antidepressants (TCAs) amitriptyline, desipramine, and imipramine (with a 40-60% favorable response), and the reversible and irreversible monoamine oxidase inhibitors (MAOIs) moclobemide and phenelzine, respectively. 

In contrast, there are a number of other uncontrolled studies and reviews describing the beneficial use of an MAOI with a tricyclic antidepressant. In addition, one study has reported switching 178 patients from tricyclics to MAOIs within 4 days or less. Of these patients, 63 were given the MAOI while still being tapered from the tricyclic, all without any apparent problems. Nevertheless, in a 6-week randomised doubleblind trial, the combinations of phenelzine or isocarboxazid plus trimi-pramine were less effective than trimipramine alone in patients with mild to moderate depression. Similarly, in a smaller randomised open study, the combination of amitriptyline and tranylcypromine was no more effective than either drug alone. ... 

A controlled trial in unselected depressed patients showed that the combination of amitriptyline (25 mg) and perphenazine (2 mg) was more effective than imipramine (25 mg).28 a doubleblind study in acutely depressed patients, comparing a combination of amitriptyline (25 mg) and fluphenazine (0.5 mg) with amitriptyline (25 mg), showed that the combination was better in relieving the symptoms associated with depression.29 Lithium carbonate was found to be highly effective in the treatment of mania but was less effective in the treatment of depression.20 The lithium salts and the tricyclic antidepres-... 

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