MAOIs Tricyclic antidepressants

SSRIs, selective serotonin reuptake inhibitors TCAs, tricyclic antidepressants MAOI, monoamine oxidase inhibitor. 

Note. ECT=electroconvulsive therapy OCD=obsessive-compulsive disorder SSRI=selective serotonin reuptake inhibitor TCA=tricyclic antidepressant MAOI=monoamine oxidase inhibitor. 

Note. SSRIs=selective serotonin reuptake inhibitors TCAs=tricyclic antidepressants MAOIs=monoamine oxidase inhibitors. 

Tricyclic antidepressants + MAOIs —> stroke, hyperpyrexia and convulsions can occur. Potentially a hazardous combination. 

Drug therapy and/or counselling are effective treatments for most patients. Three categories of drugs used as antidepressants are tricyclic antidepressants, MAOIs and SSRIs. 

Use of die MAOIs must be discontinued 2 weeks before the administration of die SSRIs. When the SSRIs are administered witii die tricyclic antidepressants, tiiere is an increased risk of toxic effects and an increased tiierapeutic effect. When sertraline is administered witii a MAOI, a potentially fatal reaction can occur. Sjymptoms of a serious reaction include hyper-tiiermia, rigidity, autonomic instability witii fluctuating vital signs and agitation, delirium, and coma Sertraline blood levels are increased when administered witii cimetidine. 

The main problems with early, irreversible MAOIs were adverse interactions with other drugs (notably sympathomimetics, such as ephedrine, phenylpropanolamine and tricyclic antidepressants) and the infamous "cheese reaction". The cheese reaction is a consequence of accumulation of the dietary and trace amine, tyramine, in noradrenergic neurons when MAO is inhibited. Tyramine, which is found in cheese and certain other foods (particularly fermented food products and dried meats), is normally metabolised by MAO in the gut wall and liver and so little ever reaches the systemic circulation. MAOIs, by inactivating this enzymic shield, enable tyramine to reach the bloodstream and eventually to be taken up by the monoamine transporters on serotonergic and noradrenergic neurons. Fike amphetamine, tyramine reduces the pH gradient across the vesicle membrane which, in turn, causes the vesicular transporter to fail. Transmitter that leaks out of the vesicles into the neuronal cytosol cannot be metabolised because... 

CYP. cytochrome P450 isoenzyme HIV, human immunodeficiency vims INR, International Normalized Ratio LFTs, liver function tests MAOI, monoamine oxidase inhibitor PT, prothrombin time TCA, tricyclic antidepressant. 

MAOI, monoamine oxidase inhibitor SARI, serotonin antagonist and reuptake inhibitor SNRI, serotonin and norepinephrine reuptake inhibitor SSRI, selective serotonin reuptake inhibitor TCA, tricyclic antidepressant. 

Virtually all types of drug that have been shown to be effective in major depression exert profound effects on the functioning of the serotoninergic or noradrenergic systems, or both. Although some treatments have been shown to decrease the sensitivity of certain postsynaptic 5-HT and NE receptors, it is generally believed that it is an enhancement of neurotransmission in these systems that is responsible for the improvement of the core symptoms of depression. For instance, long-term administration of tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) decreases the density of (3-adrenoceptors and cortical 5-HT2 receptors (Blier and Abbott 2003). 

In addition to this serious diet-drug interaction, irreversible MAOIs also potentiate the effects of sympathomimetic drugs like ephedrine found in over-the-counter cold remedies and recreational stimulants like amphetamine. The MAOIs also interact with drugs that increase synaptic concentrations of 5-HT, such as the tricyclic antidepressant clomipramine and the herbal SSRI antidepressant St John s wort (Hypericum spp.). The resulting serotonin syndrome is characterised by hyperthermia and muscle rigidity. While devoid of these side effects the reversible MAO-A inhibitor moclobemide has yet to establish itself as a first-line alternative to the SSRIs. 

A number of medications used in the treatment of anxiety have effects on serotonin neurotransmission (Ch. 13). These medications include tricyclic antidepressant medications, SSRIs, and monoamine oxidase inhibitors (MAOIs). However, because these medications take weeks to exert their full anxiolytic effects, it is unlikely that blocking the reuptake (and thus increasing synaptic levels) of either serotonin or norepinephrine selectively is responsible for their anxiolytic properties — rather it is suspected that the therapeutic effects are due to changes in gene expression, protein levels, and eventually changes in synaptic connections between neurons. 

AUC, area under the curve, Cmax, maximum concentration MAOI, monoamine oxidase inhibitor TCA, tricyclic antidepressant. Recommended first-line drug interaction search engines Lexi-Comp, Inc Lexi-Comp Online, http //online.lexi.com and Thomson MICROMEDEX Healthcare Series https //www.thomsonhc.com. 

Tricyclic Antidepressants (TCAs). The TCAs were also introduced in the 1950s, and some were discovered to be effective anxiolytics in the 1960s. For example, early studies pioneered by Donald Klein and his colleagues indicated that imipra-mine (Tofranil) effectively relieved panic attacks. Like the MAOIs, the TCAs are not addictive but also require over 3 weeks to begin to achieve significant therapeutic benefit for anxiety. 

The development of specific drugs for the treatment of depression only occurred in the early 1950s with the accidental discovery of the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs). This period marked the beginning of the era of pharmacopsychiatry. 

Changing a patient from one MAOI to another, or to a TCA, requires a "wash-out" period of at least 2 weeks to avoid the possibility of a drug interaction. There is evidence to suggest that a combination of an MAOI with clomipramine is more likely to produce serious adverse effects than occurs with other TCAs. Regarding the newer non-tricyclic antidepressants, it is recommended that a "wash-out" period of at least 5 weeks be given before a patient on fluoxetine is given an MAOI this is due to the very long half-life of the main fluoxetine metabolite norfluoxetine. 

Citalopram is a selective serotonin re-uptoke inhibitor (SSRI). These tend to have fewer ontimuscarinic effects than tricyclic antidepressant (TCA) drugs, such as dry mouth and constipation however, SSRIs tend to cause gastrointestinal effects, such as nausea and vomiting. MAOIs are monoamine oxidase inhibitors. 

Drugs that may be affected by duloxetine include drugs extensively metabolized by CYP2D6 (eg, flecainide, phenothiazines, propafenone, tricyclic antidepressants, thioridazine), alcohol, CNS-acting drugs, MAOIs, and drugs highly bound to plasma proteins (eg, warfarin). 

MAOIs should not be administered together with or immediately following tricyclic antidepressants (TCAs). At least 14 days should elapse between the discontinuation of the MAOIs and the institution of a TCA. Some TCAs have been used safely and successfully in combination with MAOIs. 

Drugs that may affect methylphenidate include MAOIs. Drugs that may be affected by methylphenidate hydrochloride include guanethidine, anticonvulsants (eg, phenytoin, phenobarbital, primidone), selective serotonin reuptake inhibitors, coumarin anticoagulants, and tricyclic antidepressants. 

Dmg-induced serotonin syndrome is generally mild and resolves when the offending drugs are stopped. However, it can be severe and deaths have occurred. A large number of drugs have been implicated including tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), pethidine, lithium, and dextromethorphan. The most severe type of reaction has occurred with the combination of selective serotonin re-uptake inhibitors and monoamine oxidase inhibitors. Both non-selective MAOIs such as phenelzine and selective MAOIs such as moclobemide and selegiline have been implicated. 

The growth during the 1990s in the use of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), for the treatment of anxiety disorders represented a major advance in the pharmacotherapy of anxiety. The efficacy of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) had been established alongside their antidepressantw actions several decades... 

With the introduction of the SSRIs, the safety and tolerability of antidepressants improved remarkably. As a class, these medications have little or no affinity for cholinergic, (3-adrenergic or histamine receptors and do not interfere with cardiac conduction. They are well tolerated by patients with heart disease and by the elderly, who are especially sensitive to the anticholinergic and orthostatic effects of the tricyclic antidepressant agents (TCAs) and monoamine oxidase inhibitors (MAOIs). 

Medications with serotonergic activity may also have other monaminergic or sympathomimetic activity. Combining MAOIs with these medications may result in a complex side effect profile. For example, combining meperidine or dextromethorphan with MAOIs may result in respiratory depression, in addition to symptoms of serotonin excess. Furthermore, interactions between MAOIs and tricyclic antidepressants (TCAs) more commonly result in potentiating shared adverse events such as othostatic hypotension, as opposed to hyperadrenergic crises or the serotonin syndrome. 

Bupropion was developed over 30 years ago in an attempt to synthesize a novel antidepressant. Researchers wanted the agent to be efficacious for the existing screening models, but be different structurally and biochemically from the tricyclics and MAOIs. The compound was to be devoid of sympathomimetic, anticholinergic, and cardiac depressant effects (Soroko and Maxwell, 1983). 

Ryan, N.D., Puig-Antich, J., Rabinovich, H., Fried, J., Ambrosini, P., Meyer, V., Torres, D., Dachille, S., and Mazzie, D. (1988). MAOIs in adolescent majot depression unresponsive to tricyclic antidepressants. J Am Acad Child Adolesc Psychiatry 27 755— 758. 

Most child and adolescent studies published thus far have focused on the effects of the tricyclic antidepressants (TCAs) and, more recently, the SSRIs. A few open studies have also shown that monoamine oxidase inhibitors (MAOIs) can be used safely with children and adolescents (Ryan et ah, 1988b), but noncompliance with dietary requirements may present a significant problem for minors. Other antidepressants, including the heterocyclics (HTC) (e.g., amoxapine, maprotiline), buproprion, venlafaxine, and nefazodone, have been found to be efficacious for the treatment of depressed adults (APA, 2000), but they have not been well studied for the treatment of MDD in children and adolescents. Therefore, this chapter mainly describes the use of SSRIs and TCAs for youth with MDD. 

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