Imipramine studies/trials

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. 

In case you think that six months may not be long enough, note that similar results were shown in a year-long industry-sponsored continuation trial comparing two different antidepressants (Seroxat and imipramine) to placebo. In that study, patients who had responded to either of the antidepressants or to the placebo during the initial six-week trial were kept on their treatment for an additional year. Patients in all three groups maintained their improvement. In fact, at the end of the one-year period, those who had been treated by placebos were the... 

Tricyciic Antidepressants (TCAs). There has been surprisingly little study of TCAs in the treatment of social anxiety disorder. Early trials with imipramine and clomipramine suggested they might be beneficial however, subsequent controlled studies indicate that TCAs are no more effective than placebo. Consequently, they are not used to treat social anxiety disorder. 

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. 

A multicenter trial comparing more appropriate doses of imipramine (75 mg twice daily, N = 167) and St. John s wort extract (250 mg twice daily standardized to 0.2% hypericin, N = 157) showed no difference in efficacy after 6 weeks of treatment. However, St. John s wort seemed to reduce anxiety symptoms more often than imipramine and was better tolerated (Woelk, 2000). A study including 240 participants compared St. John s wort with fluoxetine in mild to moderate depression and also concluded that efficacy of both treatments was comparable (Schrader, 2000). These results have been replicated in a smaller trial us-... 

Beginning in the 1960s, a number of agents, including lysergic acid diethylamide, methysergide, levodopa, triiodothyronine, imipramine, and 5-hydroxytrypto-phan were studied in autistic disorder. Many of these trials were limited by the lack of diagnostic standard-... 

There have been three randomized clinical trials and multiple case reports and open-label trials with the tricyclic antidepressants (TCAs) in PTSD, although only one study of childhood PTSD (Southwick et al., 1994) has been reported. Robert et al. (1999) reported the use of low-dose imipramine (1 mg/kg) to treat symptoms of ASD in children with burn injuries. In this study, 25 children ages 2 to 19 years were randomized to receive either chloral hydrate or imipramine for 7 days. Ten of 12 subjects receiving imipramine experienced from half to full remission of ASD symptoms, whereas 5 of 13 subjects responded to chloral hydrate. Sleep-related flashbacks and insomnia appeared to be particularly responsive to treatment. 

Because many antidepressant compounds are also effective in panic disorder, we performed a trial of inositol in panic (Benjamin et al. 1995). Twenty-one patients with panic disorder with or without agoraphobia completed a double-blind, random assignment crossover treatment trial of inositol 12 g/ day versus placebo, with 4 weeks in each treatment phase. Frequency of panic attacks and severity of panic disorder and of agoraphobia declined significantly more on inositol than on placebo the effect was comparable to that of imipramine in previous studies. Side effects were minimal. 

Some questions have been raised about the relative efficacy of the SSRls, particularly in severe depression. The pooled analyses of the data from blinded, controlled trials have tended to find similar levels of efficacy between the SSRls and the comparator TCA, imipramine. Paroxetine and fluvoxamine were both found in subanalyses of patients with severe depression included in large placebo- and imipramine-controlled studies to be more effective than imipramine in severe depression (S. A. Montgomery 1992a Ottevanger 1991 Tignol et al. 1992 Wakelin 1988]. However, imipramine may not be the TCA that is most effective in severe depression or may not have been used in the trials at an adequate dose. 

Efficacy. To date, more than 15 clinical trials have been conducted comparing fluvoxamine with other active agents and placebo. Imipramine was the most common comparator drug used, and studies have indicated that fluvoxamine was effective as the reference drug, although significantly supe-... 

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. 

Bakish D, Hooper CL, Filteau MJ, et al A double-blind placebo-controlled trial comparing fluvoxamine and imipramine in the treatment of panic disorder with or without agoraphobia. Psychopharmacol Bull 32 135-141, 1996 Bakish D, Hooper CL, Thorton MD, et al Fast onset an open study of the treatment of major depressive disorder with nefazodone and pindolol combination therapy. Int Clin Psychopharmacol 12 91-97, 1997 Baldwin DS Depression and sexual function. J Psychopharmacol 10 (suppl l) 30-34, 1996... 

Rickels K, Schweizer E, Clary C, et al Nefazodone and imipramine in major depression a placebo-controlled trial. Br J Psychiatry 164 802-805, 1994 Riddell EG Studies on Li" transport using 7Li and 61i nuclear magnetic resonance, in Lithium and the Cell. Edited by Birch NJ. San Diego, CA, Academic Press, 1991, pp 85-98... 

Treatment of GAD can be undertaken using a number of pharmacological agents. Benzodiazepines have been found to be superior to placebo in several studies and all benzodiazepines appear to be equally effective. However, side effects include sedation, psvchomotor impairment, amnesia and tolerance (Chapter 1). Recent clinical data indicate that SSRIs and SNRIs are effective in the treatment of acute GAD symptoms. Venlafaxine, paroxetine and imipramine have been shown to be effective antianxiety medications in placebo-controlled studies. Case studies also indicate the usefulness of clomipramine, nefazodone, mirtazapine, fluoxetine and fluvoxamine in GAD. Buspirone, a 5-HTla receptor partial agonist, has been shown to be effective in several placebo-controlled, double-blind trials (Roy-Byme and Cowley, 2002). Buspirone has a later onset of action than both benzodiazepines and SSRIs but with the advantage of being non-addictive and non-sedating. 

A larger set of placebo-controlled studies show conclusively that imipramine is also effective for the treatment of panic disorders. Other agents shown to be effective in panic disorders include the SSRIs paroxetine, sertraline, fluvoxamine, fluoxetine and citalopram. Generally, initial treatment of moderate to severe panic disorders may require the initiation of a short course of benzodiazepines e.g. clonazepam (0.5 1 mg twice daily), and an SSRI. The patient will obtain immediate relief from panic attacks with the benzodiazepine whereas the SSRI may take 1 6 weeks to become effective. Once a patient is relieved of initial panic attacks, clonazepam should be tapered and discontinued over several weeks and SSRI therapy continued thereafter. There are no pharmacological treatments available for specific phobias, however controlled trials have shown efficacy for several agents, e.g. phenelzine, moclobemide. clonazepam, alprazolam, fluvoxamine. sertraline and paroxetine in the treatment of social phobia (Roy-Byrne and Cowlev, 2002). 

Few data are available to guide this decision beyond clinical experience. There is a modest amount of evidence that nonresponders to TCAs, principally desipramine or imipramine, alone may respond to a SSRI alone and vice versa (136). No compelling evidence exists showing that nonresponders to one SSRI as a result of a lack of efficacy will respond to a second trial with another SSRI. There is limited confidence in the results of studies that have been done switching nonresponders from one SSRI to another for two reasons. First, virtually all have been open label and, second, most were conducted by the manufacturer of the second SSRI. Until there is more substantive evidence that switching from one SSRI to another is worthwhile, it may be more prudent to switch to a class of antidepressants with a different putative mechanism of action. 

Most efficacy trials with reboxetine have so far only been published in review articles ( 178). Most of these articles did not have peer review and do not contain the full details concerning methodology or results. This fact limits the ability to accurately determine its relative efficacy and tolerability. In short-term (4 to 8 weeks), placebo-controlled clinical trials, reboxetine produced a response (defined as at least a 50% reduction in severity scores) in 56% to 74% of patients. These results were statistically superior to placebo in most studies. Reboxetine was also found to be as effective as imipramine and desipramine in four double-blind, randomized, active-controlled (but not placebo-controlled) studies involving more than 800 outpatients or inpatients with major depression. Reboxetine produced equivalent antidepressant response rates compared with fluoxetine in two clinical trials, one of which was also placebo-controlled. However, reboxetine was reported to have improved social motivation and behavior more than fluoxetine as assessed by the newly developed Social Adaptation Self-Evaluation Scale. In all of the studies, reboxetine had a similar time (i.e., 2 to 3 weeks) to onset of the antidepressant efficacy as do other antidepressants. 

As a results of these studies, clinicians have proposed that switching to reboxetine or bupropion might a useful strategy given that these antidepressants share the ability with desipramine and imipramine to block NE uptake. Nevertheless, only one small open label study has been done to test this possibility ( 365). If bupropion is to be used in patients switched from an ineffective trial of fluoxetine, the dose should be kept low for several weeks to allow for the clearance of fluoxetine and norfluoxetine. Case reports indicate that fluoxetine can elevate levels of the active metabolites of bupropion, which, in turn, could mediate an increase risk of adverse effects (366). 

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). 

Pheneizine The efficacy of both reversible and irreversible MAOIs for the treatment of PTSD has been studied in controlled trials. Phenelzine has been shown to be superior to placebo and imipramine in patients with chronic PTSD who had a very low placebo response ( 271, 283). Thus, we believe phenelzine is worth trying for patients who can adhere to dietary and medicinal restrictions. 

Of the antidepressants available, imipramine is the most extensively studied. A trial assessing this agent s effectiveness for alcoholism with co-morbid depression had certain advantages over its predecessors, including the following ... 

Regarding the drug treatment of depression in children, there is so far a paucity of good clinical trials to show that antidepressants are effective. Several small studies suggest that daily doses of up to 5mg/kg of imipramine may be beneficial, but there is no data to show whether other types of antidepressant medication are effective. The side effects and toxicity of tricyclic antidepressants are legion and have been discussed in detail elsewhere. Undoubtedly the SSRIs should now be the drugs of first choice in the treatment of depression in children. 

The DSM-IV classifies anxiety disorders in children into four categories, namely social anxiety, over-anxious disorder, phobias and separation anxiety. Only separation anxiety, a fear of losing a loved one or a close attachment, has been reasonably well studied from the point of view of drug treatment. School phobia is perhaps the most severe form of separation anxiety and there are several trials to show that imipramine, in daily doses of up to 5mg/kg, is effective. Many patients require drug treatment for at least 6 to 8 weeks before an optimal response is achieved. Frequently, children remain symptom free after a 3M month course of treatment. In addition to the usual anticholinergic effects of imipramine, it should be noted that children are often susceptible to withdrawal symptoms such as nausea and gastrointestinal spasm. This may be reduced if the drug is slowly withdrawn over a 2-week period. 

In addition to known antidepressants increasing endogenous opioids, opioid ligands have also been administered to depressed patients to determine if opioid compounds have clinical efficacy to treat depression. The opioid ligand cyclazocine improved symptoms in severely depressed, chronically ill mental patients in an open clinical trial and in clinical trials with patients unresponsive to the tricyclic antidepressant imipramine [16]. Intravenous (5-endorphin infusions improved mood in depressed patients in open case studies [17] and in depressed patients in a double-blind placebo-controlled study [18,19]. However, one study found a trend to improve depression scores in patients after acute and chronic (5-endorphin infusions, but it was not significant [20]. 

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