Selective Serotonin compared

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. 

The selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of 5-HT into the presynaptic neuron. They are generally chosen as first-line antidepressants because of their safety in overdose and improved tolerability compared to earlier agents. 

The traditional scheme is complicated by the fact that some antidepressants exhibit characteristics of more than one class. For example, clomipramine, a tricyclic antidepressant (TCA) with side effects and toxicity similar to other TCAs, works more like the selective serotonin reuptake inhibitors (SSRls). Similarly, venlafaxine and duloxetine, which are usually grouped with the atypical antidepressants, have a side effect and safety profile comparable to the SSRls. Although a classihcation system based on mechanism of action offers some advantage (see Table 3.7), even this scheme is limited by the fact that antidepressants that work in the same way may have widely divergent side effect and safety profiles. In the following discussion, the traditional classification system is adopted. Although fraught with problems and inconsistencies. 

Other Antidepressants. Antidepressant refinements for the next 30 years primarily consisted of the development of new TCAs. However, in 1988, a novel antidepressant class, the selective serotonin reuptake inhibitors (SSRIs), was introduced in the United States. The chief innovation of the SSRIs was that they afforded the comparable effectiveness of the TCAs with fewer side effects and minimal toxicity. The debut of the SSRIs coincided with the reworking of the nosology of the anxiety disorders in DSM-III and DSM-IV. As a result, the SSRIs have been studied extensively in each of the respective anxiety disorders and in many cases have obtained FDA approval for the treatment of one or more of these anxiety syndromes. The SSRIs currently available in the United States include citalopram (Celexa), escitalo-pram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). 

The field of antidepressant research was revolutionized in the late 1980s by the introduction of selective serotonin reuptake inhibitors (SSRIs), exemplified by fluoxetine (9). In addition to their antidepressant action, SSRIs have also proven effective for a broad range of psychiatric illnesses, and, more importantly, they demonstrated an improved tolerability profile as compared to TCAs and MAOIs due to their increased selectivity. On the other hand, SSRIs proved inferior to TCAs and MAOIs in their reduced antidepressant effects, slower onset of action, lower remission rates, and decreased ability to control the physical symptoms associated with depression. 

Smith D, Dempster C, Glanville I, et al. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants a meta-analysis. Br 1 Psych iatry 2002,180 396-404. 

The efficacy of beta-blockers in the symptomatic relief of anxiety in adults has been established in over a dozen controlled trials (Neppe, 1989). In a number of countries, beta-blockers have been licensed for the treatment of anxiety disorders. Somatic manifestations of anxiety such as palpitations, diaphoresis, and tremor, rather than core psychological symptoms, were particularly responsive to beta-blocker treatment. In comparative trials that included patients with severe anxiety and panic attacks, the antianxiety effect of beta-blockers was, however, somewhat less powerful than that of benzodiazepines (Lader, 1988), with the exception of a small trial that compared alprazolam to propranolol (Ravaris et ah, 1991). Head-to-head comparisons of beta-blockers and selective serotonin reuptake inhibitors (SSRIs) are lacking. Performance and stress-related anxiety that may affect public performers, such as musicians or people taking an examination or giving a speech, seems to be particularly suited for beta-blocker treatment (Lader, 1988). Beta-blockers may be given on an as-required basis 1-2 hours before the stressful situation. 

Anderson DN, Wilkinson AM, Abou-Saleh MT, et al Recovery from depression after electroconvulsive therapy is accompanied by evidence of increased tetra-hydrobiopterin-dependent hydroxylation. Acta Psychiatr Scand 90 10-13, 1994 Anderson IM, Cowen PJ Effect of pindolol on endocrine and temperature responses to buspirone in healthy volunteers. Psychopharmacology 106 428-432, 1992 Anderson IM, Tomenson BM Treatment discontinuation with selective serotonin reuptake inhibitors compared with tricyclic antidepressants a meta-analysis. BMJ 310 1433-1438, 1995... 

Roose SP, Glassman AH, Walsh BT, et al Tricyclic nonresponders phenomenology and treatment. Am J Psychiatry 143 345-348, 1986 Roose SP, Glassman AH, Attia E, et al Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 151 1735-1739, 1994... 

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... 

We have provided a summary of the results from double-blind, random-assignment studies (usually class I or II designs) comparing HCAs, selective serotonin reuptake inhibitors (SSRIs), other new antidepressants, and MAOIs with placebo or with each other for the acute treatment of depression. Each study was reviewed, and a global judgment made, based on all the evidence presented, as to whether a given drug was more effective than placebo or another control therapy. 

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). 

The most recent systematic review and meta-analysis involved 37 randomized, double-blind, controlled trials (26 compared St. John s wort to placebo, 7 to tricyclic antidepressants, and 7 to selective serotonin reuptake inhibitors [SSRIs]). St. John s wort was reported to be more efficacious than placebo and equivalent to prescription reference treatments including the SSRIs for mild to moderate depression. Most trials used 900 mg/d (for mild to moderate depression) of St. John s wort for 4-12 weeks. 

MacGillivray S, Arroll B, Hatcher S, et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care systematic review and metaanalysis. BMJ. 2003 326 1014. 

Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM. 2003 96 369-374. 

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. 

The selective serotonin-reuptake inhibitors (SSRI) are a new group of chemically unique antidepressant drugs that specifically inhibit serotonin reuptake (see Figure 12.3). This contrasts with the tricyclic antidepressants that nonselectively inhibit the uptake of norepinephrine, and serotonin, and block muscarinic, H histaminic and a -adrenergic receptors. Compared with tricyclic antidepressants, the SSRIs cause fewer anticholinergic effects and lower cardiotoxicity. However, the newer serotonin reuptake inhibitors should be used cautiously until their long-term effects have been evaluated. 

Psychodynamic supportive psychotherapy (n = 107) has been compared with psychotherapy plus medication (n = 101) in patients with major depressive disorder (93). The medications included venlafaxine, selective serotonin reuptake inhibitors, nortriptyline, and nortriptyline plus lithium. Lithium was used as an augmentation strategy in the patients who took lithium and nortriptyline (number not given). There were no differences in outcomes between the two treatment groups. No adverse effects specific to lithium were reported. 

Several studies have examined the interaction between selective serotonin reuptake inhibitors (SSRIs) and P-gp and have shown that not all members of this class of drugs are P-gp substrates. Concentrations of paroxetine and venlafaxine/ but not fluoxetine/ were significantly increased in the brains of mdrla/b (—j—) knockout mice compared to concentrations in the wild-type mice.(100) In cell culture studies/ sertraline/ its metabolite desmethylsertraline/ and paroxetine were shown to be potent inhibitors of P-gp however/ citalopram and venlafaxine were only weak inhibitors (101/ 102). 

Citalopram (Celexa), a highly selective serotonin re uptake inhibitor, was evaluated in a small (n = 38) randomized placebo-controlled trial. 19 patients with BED were administered 20-60 mg of citalopram daily or matching placebo (McElroy et al. 2003). Citalopram significantly reduced the frequency of binge eating and lowered BMI compared to placebo. It was generally well tolerated. 

Selective serotonin reuptake inhibitors (SSRIs) are first-line agents when medications are indicated for BN, because of improved tolerability and safety, but they do not have superior efficacy compared with other antidepressant classes. The dose of fluoxetine in BN is higher (60 mg/day) than the dose usually used in depression. 

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