Serotonin reuptake inhibitors, selective toxicity

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). 

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). 

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). 

Rasagiline Inhibits MAO-B selectively, higher doses also inhibit MAO-A Increases dopamine stores in neurons may have neuroprotective effects Parkinson s disease adjunctive to levodopa smooths levodopa response Oral Toxicity interactions may cause serotonin syndrome with meperidine, and theoretically also with selective serotonin reuptake inhibitors, tricyclic antidepressants... 

Linezolid Prevents bacterial protein synthesis by binding to the 23S ribosomal RNA of 50S subunit Bacteriostatic activity against susceptible bacteria Infections caused by methicillin-resistant staphylococci and vancomycin-resistant enterococci Oral, IV hepatic clearance (half-life 6 h) dosed twice-daily Toxicity Duration-dependent bone marrow suppression, neuropathy, and optic neuritis serotonin-syndrome may occur when coadministered with other serotonergic drugs (eg, selective serotonin reuptake inhibitors)... 

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. 

The discovery of the antidepressant effect of medications was coincidental to their use for other disorders. Initial work published in 1952 reported that iproniazid (originally used for the treatment of tuberculosis) could elevate mood. Although the use of iproniazid was discontinued due to toxicity, many other additional medications have been tested and approved for the treatment of depression. These include monoamine oxidase inhibitors, tricyclics, selective serotonin reuptake inhibitors, and a heterogeneous class of atypical drugs. 

I warned the public and the health professions about the risk of SSRI antidepressant-induced suicidality in adults in Toxic Psychiatry (1991) and again in 1997 with a lengthy discussion in the first edition of this book. I elaborate in much greater detail on risk in 2003 in my scientific journal article Suicidality, Violence and Mania Caused by Selective Serotonin Reuptake Inhibitors (SSRIs) A Review and Analysis. ... 

Psychiatric patients often take multiple psychotropic medications and have medical illnesses that require additional pharmacother-apeutic treatments. Psychiatric practitioners must recognize that administration of multiple medications can alter pharmacokinetic profiles of compounds that are biotransformed by the CYP enzymes. For example, the addition of the popular selective serotonin reuptake inhibitor (SSRI) fluoxetine to a treatment regimen for depression that includes the TCA desipramine has been reported to produce toxic levels of the TCA because of competi-... 

Antidepressants selective serotonin reuptake inhibitors, tricyclic antidepressants Antihypertensives felodipine Antibiotics quinolones, isoniazid Bronchodilators albuterol, theophylline Corticosteroids prednisone Dopa agonists levodopa Herbals ma huang, ginseng, ephedra Nonsteroidal anti-inflammatory drugs ibuprofen Stimulants amphetamines, methylphenidate, caffeine, cocaine Sympathomimetics pseudoephedrine Thyroid hormones levothyroxine Toxicity anticholinergics, antihistamines, digoxin Withdrawal alcohol, sedatives... 

Fewer adverse effects were reported among moclobemide-treated patients compared with selective serotonin reuptake inhibitor (SSRI)-treated patients. Since moclobemide does not induce orthostatic hypotension, does not possess anticholinergic properties, and is not cardiotoxic, it is very well suited among the MAOIs for the treatment of depression. Moclobemide has limited potential to elicit a hypertensive crisis, because the pressor effect of tyramine from food is only marginally potentiated compared with tranylcypromine. The pressor effect of tyramine is normalized within 3 days of cessation of treatment with moclobemide. The combination of SSRIs and moclobemide has good efficacy in cases of refractory depression, but there is controversy as to whether toxic side-effects such as serotonin syndrome can result from this combination. Currently, more studies are needed before this combination can be recommended. Acute overdose with MAOIs causes agitation, hallucinations, hyperpyrexia, hyperreflexia, convulsions, and death. The most dangerous MAOIs in overdose are the irreversible non-selective MAOIs. T2s-27... 

Toxicity Adverse effects include insomnia, mood changes, dyskinesias, gastrointestinal distress, and hypotension. Meperidine in combination with selegiline has caused agitation, delirium, and death. Selegiline has been implicated in the serotonin syndrome when used in patients taking selective serotonin reuptake inhibitors (see Chapter 30). 

Christensen AM, Faaborg-Andersen S, Ingerslev F, Baun A (2007) Mixtiu e and singlesubstance toxicity of selective serotonin reuptake inhibitors toward algae and crustaceans. Environ Toxicol Chem 26 85-91... 

Post-2000 Renal rhabdomyolysis with the statin, cerivastin cardio-toxicity with the COX-2 inhibitor, rofecoxib and liver damage with the selective serotonin and norepinephrine reuptake inhibitor, atomoxetine. 

FIGURE 6-16. If a tricyclic antidepressant (TCA) is given together with a serotonin selective reuptake inhibitor (SSRI), the SSRI will prevent TCA metabolism. This causes TCA levels to increase, which can be toxic. Therefore either monitoring of TCA plasma concentration with dose reduction of the TCA, or avoidance of the combination, is required. 

Serotonin-Selective Reuptake Inhibitors. Since their introduction in the mid-1980s SSRIs have become the most widely used of all antidepressants. This is largely because of their improved safety and tolerability in clinical use. Although the SSRIs are no more efficacious or rapid in onset of action than the tricyclics, they lack most of the serious toxicity and adverse side effects associated with the first-generation drugs. The relative absence of cardiac toxicity makes the SSRIs relatively safe in overdose (36). Fatal overdose... 

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