Antidepressant drugs adverse effects

Although most physicians avoid the combination of an MAOl with most other antidepressants, a number of reports indicate that MAOIs combined with a TCA can be effective and safe in treatment-resistant patients. This combination should be used only by a physician skilled in their use and familiar with their potential adverse effects and drug interactions. Generally, tertiary amine TCAs have been used in combination with MAOIs. Once the dose of the TCA is established, the MAOl should be slowly added. Never attempt the reverse order without a 2-week delay. It may also be prudent to lower the TCA dose slightly before starting the MAOl. An example might be the addition of phenelzine to amitriptyline, starting with an initial dose of 15 mg and subsequent dose increments weekly as needed. The total dose of an MAOl, used in combination with TCA, is usually lower than when used alone (e.g., 30 to 60 mg per day). When the combination is discontinued, the MAOl should be stopped first. 

Endogenous biogenic amines in the brain include catecholamines [NE (noradrenaline, NA), dopamine (DA), epinephrine (adrenaline)] 5-HT, histamine, and the so-called trace amines (P-phenylethylamine, tyramine, tryptamine, and octopamine). These amines have in common a arylalkylamine stmcture, and all have been implicated in the etiology of one or more psychiatric disorders and/or in therapeutic and/or adverse effects of drugs used to treat such disorders. In this review on depression, the focus in the case of biogenic amines will be on 5-HT, NE, and DA, although epinephrine and histamine and trace amines have also been implicated (see the section on Other Antidepressant Approaches and Targets ). 

Because of their lack of selectivity and their irreversible inhibition of MAO, the first MAOIs to be developed presented a high risk of adverse interactions with dietary tyramine (see Chapter 20). However, more recently, drugs which are selective for and, more importantly, reversible inhibitors of MAO-A (RIMAs) have been developed (e.g. moclobemide). These drugs are proving to be highly effective antidepressants which avoid the need for a tyramine-free diet. 

Differentiate antidepressants according to pharmacologic properties, adverse-effect profiles, pharmacokinetic profiles, drug interaction profiles, and dosing features. 

Several antidepressants, including most of the SSRIs, nefa-zodone, and duloxetine, are known to inhibit various cytochrome P-450 isoenzymes, thereby elevating plasma levels of substrates for those isoenzymes and thus potentially leading to increased adverse effects or toxicity of those drugs. The propensity to cause these drug interactions will vary with the particular antidepressant and the precise isoenzyme9,19,30 (Table 35-6). 

Each antidepressant has a response rate of approximately 60% to 80%, and no antidepressant medication or class has been reliably shown to be more efficacious than another 22 MAOIs may be the most effective therapy for atypical depression, but MAOI use continues to wane because of problematic adverse effects, dietary restrictions, and possibility of fatal drug interactions.22,28 There is some evidence that dual-action antidepressants, such as TCAs and SNRIs, may be more effective for inpatients with severe depression than are the single-action drugs such as SSRIs,22,28 but the more general assertion that multiple mechanisms of action confer efficacy advantages is quite controversial.33... 

Evaluate patients for symptom improvement frequently (e.g., weekly) during the first 4 weeks of therapy. The goal is to alleviate panic attacks and reduce anticipatory anxiety and phobic avoidance with resumption of normal activities. Alter the therapy of patients who do not achieve a significant reduction in panic symptoms after 6 to 8 weeks of an adequate dose of antidepressant or 3 weeks of a benzodiazepine. Regularly evaluate patients for adverse effects, and educate them about appropriate expectations of drug therapy. 

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. 

Altered homeostasis in older persons can lead to important and common adverse drug effects the less robust homeostatic milieu may be stressed by drugs, causing adverse effects. Examples include orthostatic hypotension due to antihypertensives and other agents that cause a-adrenergic blockade (e.g. terazosin, doxazosin, tricyclic antidepressants and phenothiazines) in those with barorecep-tor dysfunction. Diuretics can cause hyponatraemia or hypokalaemia in older patients, whereas ACE inhibitors and NSAIDs can cause hyperkalaemia. 

Blackwell, B. (1981) Adverse effects of antidepressant drugs. Part 1 monoamine oxidase inhibitors and tricyclics. Drags 21 201-219. 

Mastering this information can be facilitated by understanding antidepressants from the perspective of their clinical pharmacology (i.e., their mechanisms of action). This is made easier by understanding how newer antidepressants were developed using the older antidepressants as a blueprint about what mechanisms could mediate an antidepressant response and what mechanisms only mediated adverse effects. Thus, it is important to understand the concept of rational drug development in psychiatry. 

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