Selective Serotonin side effects

The selective serotonin reuptake inhibitors (SSRIs) block removal of 5-HT from the synapse by transport proteins. SSRIs are not notably more effective than other antidepressants, but their inherent selectivity minimizes side effects. Numerous SSRIs have been successful in the market and are considered to be blockbuster drugs (Figure A.18). 

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. 

An important advance in this field has been made by the discovery of selective serotonin (5-HT3) receptor antagonists that are effective inhibitors of cytotoxic drug-induced emesis in laboratory animals. The new agents have been found to be free of the undesirable side-effects associated with dopaminergic blockade and have shown significant protection from emesis in early clinical trials. 

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. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

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. 

The selectivity of the SSRIs does not mean that they are totally without side effects. First, serotonin-secreting nerve cells are distributed throughout the brain and control a wide array of nervous system activities. As a result, increasing serotonin not only relieves depression, it can also produce many side effects such as abdominal discomfort, sexual dysfunction, and anxiety. Second, the selectivity of the SSRIs is not absolute but relative. Although the main action of the SSRIs is the same, they do have differences. For patients, this means that the drug interactions and side effects of the SSRIs vary somewhat. It also means that a patient who does not respond to one SSRI may respond to another. 

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). 

When we talk about serotonin-blocking medications, a point of clarification must be made. In most cases, medications do not block overall serotonin activity but instead block the activity at one of the many serotonin receptor types. For example, the antidepressants trazodone, nefazodone, and mirtazapine increase total serotonin activity yet they block certain of the serotonin receptors. Mirtazapine increases both serotonin and norepinephrine activity by interfering with the alpha-2 receptor. By also blocking the serotonin-2 and serotonin-3 receptors, mirtazapine avoids the sexual dysfunction and GI side effects commonly experienced with other serotoninboosting medications. We cannot truly call these serotonin-blocking medications, because they are serotonin-boosting medications that selectively block certain serotonin receptors. 

Several different types of serotonin receptor (for example, S-HTi / 5-HT2A/ 5-HT2C/ 5-HTib/id) have been associated with the motor side effects of the SSRIs which may arise should these drugs be administered in conjunction with a monoamine oxidase inhibitor. The 5-HT3 receptor is an example of a non-selective cation charmel receptor which is permeable to both sodium and potassium ions and, because both calcium and magnesium ions can modulate its activity, the 5-HT3 receptor resembles the glutamate-NMDA receptor. Antagonists of the 5-HT3 receptor, such as ondansetron, are effective antiemetics and are particularly useful when... 

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... 

In an attempt to combine the clinical efficacy of the TCAs with the tolerability and safety of the SSRIs and NRIs, drugs showing selectivity in inhibiting the reuptake of both noradrenaline and serotonin were developed. Being structurally unrelated to the TCAs however, they lacked their side effects including their cardiotoxicity. 

Selective serotonin re-uptake inhibitors such as paroxetine tend to cause less antimuscarinic side-effects and are less toxic in overdose than the tricylic antidepressants, such as amitriptyline. However, selective serotonin re-uptake inhibitors are more likely to cause gastrointestinal disturbances, such as nausea and vomiting, than tricylic antidepressants. Selective serotonin re-uptake inhibitors and tricylic antidepressants are equally effective. 

Selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants are equally effective. Hov/ever, SSRIs tend to have fewer antimuscarinic side-effects and are less cardiotoxic in case of overdosage. SSRIs tend to cause gastrointestinal side-effects. Both SSRIs and tricylic antidepressants exhibit a time lag before the action of the antidepressants becomes effective. 

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