Selective serotonin reuptake side effects

MDMA overdose as well as the concomitant consumption of selective serotonin reuptake inhibitors (SSRI) with other dmgs that exert serotoninergic effects (such as inhibitors of monoamine oxidase) can rapidly lead to the serotonin syndrome. Its symptoms, which are reversible upon cessation, of the drug include confusion, muscle rigidity in the lower limbs, and hyperthermia suggesting an acute reaction to serotonin overflow in the CNS. Blocking the function of SERT outside the brain causes side effects (e.g., nausea), which may be due to elevated 5HT however , impairment of transporter function is not equivalent to direct activation of 5HT recqrtors in causing adverse effects such as fibrosis and pulmonary hypertension. 

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. 

Alternatives to estrogen for hot flushes are shown in Table 31-6. Progesterone alone may be an option in women with a history of breast cancer or venous thrombosis, but side effects limit their use. For women with contraindications to hormone therapy, selective serotonin reuptake inhibitors and venlafaxine are considered by some to be first-line therapy, but efficacy of venlafaxine beyond 12 weeks has not been shown. 

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. 

Trazodone, 25 to 100 mg, is often used for insomnia induced by selective serotonin reuptake inhibitors or bupropion. Side effects include serotonin syndrome (when used with other serotonergic drugs), oversedation, a-adrenergic blockade, dizziness, and rarely priapism. 

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. 

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. 

Harmala alkaloids are potent inhibitors of monoamine oxidase (Callaway and Grob 1998). Thus, if combined with other antidepressants, such as selective serotonin reuptake inhibitors, there is potential for serious side effects. Harmaline or its metabolites also cross the placental barrier (Okonmah et al. 1988). 

Side effects can also occur quickly after a single dose of a medication. For example, some antidepressants (e.g., selective serotonin reuptake inhibitors) can cause nausea, stomach upset, loose stools, and even diarrhea. Likewise, some anti-psychotics (e.g., haloperidol (Haldol)) can cause unpleasant or painful muscle spasms called dystonias. All of these side effects can occur within minutes or hours of taking a single dose of the medication. These side effects are also a result of the direct effects of the medication in the synapse. 

Psychiatric medicines exert multiple effects for two principal reasons. First, they usually interact with more than one receptor type. There are two ways to look at this. You will often hear a medication with multiple receptor interactions called a dirty drug. This is because the more receptor interactions it has, the more effects, and hence side effects, it produces. As a result, great effort has been made to develop newer medications with fewer receptor interactions and, thus, fewer side effects. This effort has been quite successful with antidepressants, as we have moved from the effective but side effect-laden tricyclic antidepressants to newer antidepressants such as selective serotonin reuptake inhibitors. 

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). 

Serendipity has played a major role in the discovery of most classes of psychotropic drugs. For example, the observation that the first antidepressants, the tricyclic antidepressants and the monoamine oxidase inhibitors, impeded the reuptake of biogenic amines into brain slices, or inhibited their metabolism, following their acute administration to rats, provided the experimenter with a mechanism that could be easily investigated in vitro. Such methods led to the development of numerous antidepressants that differed in their potency, and to some extent in their side effects (for example, the selective serotonin reuptake inhibitors) but did little to further the development of novel antidepressants showing greater therapeutic efficacy. The accidental discovery of atypical antidepressants such as mianserin led to the broadening of the basis of the animal models... 

Antidepressant drugs, such as the tricyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs), are very important for the treatment of psychotic depression (see Chapter 34). They have been shown to be effective when used in the treatment of several anxiety disorders, including general anxiety, obsessive-compulsive disorder, and several phobias, including agoraphobia. Because the SSRIs are less toxic than the tricyclic antidepressants, their use in the treatment of anxiety is safer and less likely to produce serious side effects. 

Geriatric Considerations - Summary Bupropion has several advantages as an antidepressant agent for use in older adults. It has neither the anticholinergic or cardiac toxicities of the tricyclic antidepressants, and has fewer sexual side effects than selective serotonin reuptake inhibitors. Because this drug may lower seizure threshold, it should be used with caution in older adults with increased risk of seizures (e.g., previous stroke, early-onset Alzheimer s disease). 

Although tricyclics continue to be used today to treat childhood depression (Zito et ah, 2000), the use in children with ADHD has decreased, most likely because of its association with the sudden deaths of five children (Biederman, 1991). Furthermore, the Physician s Desk Reference (PDR) warns that MPH may inhibit the metabolism of tricyclics, but no such warning exists for DEX or (AMP). Due to the concern that children on this combination of medications are prone to develop more side effects, it is not a recommended form of treatment. Instead, MPH combined with a selective serotonin reuptake inhibitor is preferable for treating a child with ADHD and comorbid depression. 

The study of TCAs in children with OCD led directly from the use of these medications in adults with similar symptoms. Findings have shown significant advantage with both CMI and DMI over placebo in the treatment of this illness (Flament et al., 1985 deVaugh-Geiss et al., 1992). Clomipramine is the only TCA with a distinct indication from the FDA for the treatment of OCD. Use of TCAs has recently been supplanted by selective serotonin reuptake inhibitor (SSRI) medications that may have a more favorable side effect profile. 

The low side effect profile, ease of use, and powerful clinical effect of the selective serotonin reuptake inhibitors (SSRIs) revolutionized the treatment of depression and anxiety in the 1990s. The success of the SSRIs shifted the focus from noradrenergic to serotonergic mechanisms in these common disorders. 

Structure is also essential in complex biological molecules. A lot of medicines used for psychiatric illnesses such as depression rely on their ability to interact with certain proteins in the brain. For instance, a class of antidepressants—medications that alleviate the symptoms of depression—act on proteins involved with the collection (reuptake) of the chemical serotonin, and they are known as selective serotonin reuptake inhibitors (SSRIs). This class of antidepressants includes Prozac and Zoloft. Earlier medications were also effective and are still sometimes used though they produce a number of side effects, such as dietary problems. Although an SSRI can also generate potentially dangerous side effects, psychiatrists tend to observe these effects less often. (Brain chemistry is the subject of chapter 3.)... 

Tricyclic antidepressants are still prescribed today, but some patients experience side effects such as dry mouth, blurry vision, constipation, and other uncomfortable conditions. Other antidepressants have since been found that induce fewer side effects. One of the most popular is fluoxetine, which is marketed under the trade name Prozac. This drug, along with Zoloft and other antidepressants, are known to inhibit reuptake proteins specifically for serotonin. As a result, these drugs are called selective serotonin reuptake inhibitors, or SSRIs. Although some concerns have appeared because of a possible risk of suicide in young patients who take Prozac, these drugs are commonly prescribed and have proved highly effective in millions of patients. 

Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) begin to be used as antidepressants. These medications are generally effective and have fewer side effects than earlier drugs. 

MAOIs are commonly associated with treatment-emergent sexual dysfunction, including decreased libido, delayed ejaculation, anor-gasmia, and impotence. Some patients become tolerant to this side effect over time, but more often the problem persists unless the dose is reduced or another medication is used to counter the sexual side effects. The treatment of sexual side effects is discussed in the Selective Serotonin Reuptake Inhibitors section earlier in this chapter. 

Numerous antidepressants were synthesized, developed and marketed on the basis of the serotonin hypothesis. The selective serotonin reuptake inhibitors (SSRIs) are similarly effective as the older tricyclic antidepressants, but have the advantage of being less toxic and not inducing anticholinergically mediated side effects (Chapter 1). From the scientific point of view1 they represent an example of mechanistic, hypothesis-driven research and development in psychopharmacology (Chapter 2). 

Although the efficacy of tricyclic antidepressants in the treatment of unipolar depression is beyond reproach, the side-effect profile of these agents makes them less desirable as first-line therapeutic agents. Introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine in the past decade has revolutionized the treatment of depression universally. The side-effect profile of SSRIs, such as nausea, diarrhea and sexual dysfunction, is considerably more benign than that of tricyclic drugs. Multiple controlled trials have proven the efficacy of SSRIs vs. placebo (Nemeroff, 1994). Recently, a number of SNRIs (serotonin and noradrenaline reuptake inhibitors) and so-called atypical antidepressants have been marketed that may have additional advantages over SSRIs, such as more rapid onset of action (venlafaxine. mirtazapine) and low sexual side-effect potential ( bupropion, nefazodone). Additionally, it appears that venlafaxine may be more efficacious in cases of treatment-refractory depression (Clerc et al., 1994 Fatemi et al., 1999). Finally, in a recent report (Thase et al., 2001),... 

Hoping to avoid such side effects as the sleep disruption and the occasional cardiac complications of the tricyclic antidepressants, and following the principle that clean drugs are theoretically preferable to dirty ones, the pharmaceutical industry has developed the selective serotonin reuptake blockers, a third generation of chemical agents to relieve depression. 

---