Selective serotonin reuptake inhibitors clinical trials

In many clinical trials a positive control of a clinically established drug is often used for comparison purposes for example, a novel selective serotonin reuptake inhibitor (SSRI), may be compared with a more established tricyclic antidepressant, such as imipramine. The aim is to see whether the new SSRI is more efficacious or has fewer adverse side effects than the more established tricyclic (Chapter 12). In many such comparisons the new and older treatments are equally efficacious at relieving depression, but the newer drugs display fewer side effects this means that they are better tolerated by patients, so that they are more willing to continue taking the tablets. The high rates of compliance also mean that, in overall terms, newer drugs with fewer side effects tend to be more efficacious. 

Rosenbaum, J.F., Fava, M., Hoog, S.L., Acroft, R.C., and Krebs, WB. (1998) Selective serotonin reuptake inhibitor discontinuation syndrome a randomized clinical trial. Biol Psychiatry 44 77-87. 

Clinical trials have found that patients with dysthymia without a concurrent major depressive episode had a higher response rate to treatment with either a selective serotonin reuptake inhibitor (SSRI) or a tricyclic antidepressant than to placebo. These patients also experienced improvement in psychosocial functioning ( 18). 

St. John s wort (Hypericum perforatum) is a perennial wildflower indigenous to Europe, North Africa, and western Asia (Fig. 1) and has been used for medicinal purposes for over two millennia. As far back as the early 16th century, St. John s wort was used primarily to treat anxiety, depression, and sleep disorders. In the late 20th and early 21st century, St. John s wort has been recommended for the treatment of mild to moderate depression (7). In support of its use for the treatment of mild to moderate depression, a number of clinical trials have demonstrated that St. John s wort has comparable efficacy to the tricyclic antidepressants (i.e., imipramine) and selective serotonin reuptake inhibitors (e.g., fluoxetine and paroxetine) (8-13). 

Clinical reports, prescription databases, and a few trials support the use of selective serotonin reuptake inhibitors in combination with the older tricyclics, especially desipramine with bupropion and, most recently, with mirtazapine in patients who do not show an adequate response to a single agent. 

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. 

Chronic pain patients tend to have concurrent depression however, the antidepressants chosen may not have any pain-relieving properties. Antidepressants that affect one neurotransmitter in the brain, such as selective serotonin reuptake inhibitors have not appeared to be effective in the management of pain in clinical trials. Antidepressants that affect multiple neurotransmitters— namely, serotonin and norepinephrine—have been shown to be effective pain relievers.Two published metaanalyses have shown that tricyclic antidepressants amitriptyline, desipramine, imipramine, and nortriptyline are the most effective treatment for the management of neuropathic pain. ° These publications review the published clinical trial data for all agents available for the management of neuropathic pain. 

Papakostas GI, Fava M. A meta-analysis of clinical trials comparing milnacipran, a serotonin -norepinephrine reuptake inhibitor, with a selective serotonin reuptake inhibitor for the treatment of major depressive disorder. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol 2007 17(l) 32-36. 

D. Selective norepinephrine and serotonin reuptake inhibitors. Both Venlafaxine and Duloxetine have shown significant higher effect than placebo in the treatment of pain in diabetic patients and both compounds are being used with increasing frequency in these patients. Duloxetine is a more potent inhibitor than Venlafaxine and seems from clinical studies to be more efficacious. Doses tested in trials are 60 and 120 mg/day and side effects include nausea, somnolence, dizziness, dry mouth and decreased appetite. 

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. 

---