Selective serotonin reuptake inhibitors depression

After a almost 30-year dominance of TCAs in the treatment of depression, selective serotonin reuptake inhibitors (SSRIs) were introduced in the 1980s. Since then, these drugs have also been used in the treatment of chronic pain (Ansari, 2000). SSRIs appear to be less effective in most patients than TCAs. Meta-analyses have shown that, in general, TCAs seem to be more effective... 

Treatment of Major Depression. Dmgs commonly used for the treatment of depressive disorders can be classified heuristicaHy iato two main categories first-generation antidepressants with the tricycHc antidepressants (TCAs) and the irreversible, nonselective monoamine—oxidase (MAO) inhibitors, and second-generation antidepressants with the atypical antidepressants, the reversible inhibitors of monoamine—oxidase A (RIMAs), and the selective serotonin reuptake inhibitors (SSRIs). Table 4 fists the available antidepressants. 

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. 

Briggs G, Freeman R, Yaffe S Drugs in Pregnancy and Lactation A Reference Guide to Maternal and Fetal Risk. Philadelphia, Lippincott, Williams Wilkins, 2002 Chengappa KN, Kambhampati R, Perkins K, et al Bupropion sustained release as a smoking cessation treatment in remitted depressed patients maintained on neatment with selective serotonin reuptake inhibitor antidepressants. J Clin Psychiatry 62 503—508, 2001... 

The enantiomerically pure 3-arylglutaric ester are precursors for the synthesis of (—)-paroxetine [10], a selective serotonin reuptake inhibitor used in the treatment of depression, obsessive compulsive disorder, and panic, and (i )-Baclofen [11], a GABAb receptor agonist, which is used cHnically in the treatment of spasticity (Chart 5.1). 

Anderson IM, Tomenson BM (1994). The efficacy of selective serotonin reuptake inhibitors in depression a meta-analysis of studies against tricyclic antidepressants. / Psychopharmacol 8, 238 9. 

There is, however, a unique risk in the bipolar form that antidepressant treatment may trigger a switch into mania. This may occur either as the natural outcome of recovery from depression or as a pharmacological effect of the drug. Particular antidepressants (the selective serotonin reuptake inhibitors) seem less liable to induce the switch into mania than other antidepressants or electroconvulsive therapy. Treatment for mania consists initially of antipsychotic medication, for instance the widely used haloperidol, often combined with other less specific sedative medication such as the benzodiazepines (lorazepam intramuscularly or diazepam orally). The manic state will usually begin to subside within hours and this improvement develops further over the next 2 weeks. If the patient remains disturbed with manic symptoms, additional treatment with a mood stabilizer may help. 

A number of non-hormonal therapies have been studied for symptomatic management of vasomotor symptoms, including antidepressants [e.g., selective serotonin reuptake inhibitors (SSRIs) and venlafaxine], herbal products (e.g., soy, black cohosh, and dong quai), and a group of miscellaneous agents (e.g., gabapentin, clonidine, and megestrol). The choice of therapy depends on the patient s concomitant disease states, such as depression and hypertension, and the risk for potential adverse effects. 

Altered removal of a neurotransmitter from the synaptic cleft. The third mechanism by which drugs may alter synaptic activity involves changes in neurotransmitter reuptake or degradation. A very well known example of a drug in this category is Prozac (fluoxetine), which is used to treat depression. The complete etiology is unknown, but it is widely accepted that depression involves a deficiency of monoamine neurotransmitters (e.g., norepinephrine and serotonin) in the CNS. Prozac, a selective serotonin reuptake inhibitor, prevents removal of serotonin from the synaptic cleft. As a result, the concentration and activity of serotonin are enhanced. 

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. 

Selective serotonin reuptake inhibitors are considered to be less effective than TCAs for migraine prophylaxis and should not be considered first- or second-line therapy. However, they may be beneficial when depression is a significant contributor to headache. Preliminary data suggest a possible benefit with venlafaxine. 

Treatment with a selective serotonin reuptake inhibitor is usually initiated in depressed patients with AD. Paroxetine causes more anticholinergic side effects than the other selective serotonin reuptake inhibitors. Ven-lafaxine may also be used. 

FIGURE 70-1. Algorithm for treatment of uncomplicated major depression. (SSRI, selective serotonin reuptake inhibitor.)... 

Some failures will be due to the presence of variants in drug handling. Patients who are rapid acetylators of isoniazid have a slower antituberculous response than slow acetylators (Evans and Clarke, 1961). Asthmatics who do not respond well to (32-agonist bronchodilators may have fewer functioning p2-adrenergic receptors (Drysdale et al., 2000). Variations in the synthesis or structure of the serotonin transporter protein, which is involved in selective reuptake of serotonin by presynaptic neurons, may explain why some patients with depressive disorders respond to selective serotonin reuptake inhibitors and others do not (Steimer et al., 2001). 

The most commonly used therapies for anxiety and depression are selective serotonin reuptake inhibitors (SSRIs) and the more recently developed serotonin noradrenaline reuptake inhibitors (SNRIs). SSRIs, which constitute 60% of the worldwide antidepressant and antianxiety market, are frequently associated with sexual dysfunction, appetite disturbances and sleep disorders. Because SSRIs and SNRIs increase 5-HT levels in the brain, they can indirectly stimulate all 14 serotonergic receptor subtypes [2,3], some of which are believed to lead to adverse side effects associated with these drugs. Common drugs for short-term relief of GAD are benzodiazepines. These sedating agents are controlled substances with addictive properties and can be lethal when used in combination with alcohol. The use of benzodiazepines is associated with addiction, dependency and cognitive impairment. 

Landen, M., Eriksson, E., Agren, H. and Fahlen, T. (1999) Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. Journal of Clinical Psychopharmacology, 19, 268-271. 

There are numerous antidepressant medications on the market (table 7.1). Following development of monoamine oxidase (MAO) inhibitors were tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and several atypical antidepressants (Baldessarini 1996). Successive generations of antidepressants have not necessarily become more effective in treating depression, but rather offer more favorable side-effect profiles—a crucial factor in effective clinical pharmacotherapy. An effective medication is not useful if its side effects are intolerable. 

A breakthrough in the treatment of major depression was the discovery of fluoxetine, marketed as Prozac. Fluoxetine has a mechanism of action similar to that of imipramine with an important exception. It is a selective serotonin reuptake inhibitor, an SSRI. This strongly suggests that, in some sense, the symptoms of major depression result from a deficit in serotonin specifically. By inhibiting its reuptake from the synapse, the activity of serotonin is enhanced. Two other important drugs for major depression, sertraline (Zoloft) and paroxetine (Paxil), among several others,... 

The TCAs were once widely used to treat depression in brain-injured patients, but they have been replaced as first-line treatments by the so-called selective serotonin reuptake inhibitors (SSRIs) including citalopram (Celexa), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and, most recently. 

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