Preparation of the Patient
Good preparation and reassurance are essential. Side effects – even relatively benign ones – are a major cause of treatment non-adherence. Drop-out rates ranging from 7 to 44% have been reported in various studies of TCAs, and from 7 to 23% in studies of serotonin reuptake inhibitors (Cookson, 1993). Proper educa-tion and reassurance about side effects can help reduce this rate. It should help reassure the patient that many of the side effects di-minish with time, or with an adjustment of dose. It may also help frame side effects in a positive light, as they represent concrete evidence that the medication is exerting its effect on the body.
The best approach may be to consider both frequency and clinical importance. That is, one should discuss those side effects that are likely to occur, as well as considering the rare but poten-tial dangerous or irreversible side effects that should be discussed (Table 79.3 and Table 79.4).
It is useful to divide side effects into “predictable” and idiosyn-cratic effects. Predictable side effects result from known pharma-cological actions of the drug. Idiosyncratic side effects are not well understood. A number of authors have written important, and very complete reviews of medication-related side effects (e.g., Cookson, 1993; Nierenberg, 1992; Mir and Taylor, 1997; Richelson, 2001); what is intended in the following paragraphs and figures is a brief summary that incorporates data from those works.
These side effects are the result of the action of the agent at vari-ous neurotransmitters and enzyme sites. The major neurotrans-mitters affected by antidepressants are as follows.
Blockade of this receptor produces a variety of peripheral and central effects. Gastrointestinal effects include decreased saliva-tion and decreased peristalsis. Decreased salivation is the most common of these effects and can cause drying of the mucous membranes. Such drying can exacerbate gum disease and den-tal caries. Decreased peristalsis can cause constipation and, in the extreme, paralytic ileus. Contraction of the bladder wall is inhibited, causing urinary hesitancy and even urinary retention. In the case of TCAs, concomitant sympathomimetic effects that cause constriction of the bladder neck and urethra worsen this ef-fect on urination. Inhibition of the parasympathetically mediated accommodation reflex, in which the ciliary body muscles nor-mally contract to thicken the lens and focus near objects on the retina, results in blurry vision and mydriasis. Such accommoda-tion paresis can occur without other anticholinergic side effects. A more serious ocular effect is the precipitation of acute narrow-angle glaucoma, through pupillary dilatation. The iatrogenic pre-cipitation of narrow-angle glaucoma through antidepressant use is quite rare. Anticholinergic cardiac effects include decreased vagal tone that can cause tachycardia. Central nervous effects in-clude impaired memory and cognition. In severe cases, such cog-nitive impairment can reach the point of a delirium. Central anti-cholinergic effects can also worsen existing tardive dyskinesia.
These effects are usually dose-related, and are worse in people with preexisting defects. For example, the cardiac effects are of most concern in those with preexisting cardiac defects, and urinary blockade generally occurs only in the presence of prostatic hypertrophy. These side effects are also more common in patients taking other anticholinergic medications, which is a common feature of many over-the-counter preparations.
MAOIs have little direct effect on receptors, and their side effects relate to enzymatic inhibition, thus they are not included in this section.
Blockade of the histamine H1-receptor is typically associated with sedation. Histamine blockade may also cause orthostatic hypo-tension and weight gain. It can impair psychomotor coordination and cause falls in the elderly. Cognitive impairment can occur as well. H2-receptor blockade causes decreased gastric acid produc-tion. This is the mechanism of many anti-ulcer medications.
Synaptic increases in norepinephrine, through either inhibition of norepinephrine reuptake or decrease in MAO degradation, cause sympathomimetic effects. Increases in norepinephrine can cause anxiety, tremors, diaphoresis and tachycardia. This tachycardia can potentiate anticholinergic cardiac effects. As noted, sym-pathomimetic effects on the bladder neck and urethra can poten-tiate the anticholinergic inhibition of normal urinary function.
Blockade of alpha-1-receptors occurs as a chronic effect through both downregulation and desensitization of the beta- and alpha-2-receptors. Blockade of the noradrenergic alpha-1-receptor is responsible for postural hypotension. In the elderly or medically ill, this postural hypotension can be significant, and lead to diz-ziness or falls. It may also be responsible for ejaculatory delay or impotence. Other potential effects include reflex tachycardia and memory dysfunction.
Potentiation of serotonin can cause anorexia, nausea, vomiting, diarrhea, “jitteriness” and anxiety. Akathisia, a syndrome of mo-tor restlessness usually associated with antipsychotics, may result from either the general effect of serotonin potentiation or the direct effects on the basal ganglia. The latter hypothesis is supported by the fact that the serotonin reuptake inhibitors – fluoxetine (Steur, 1993), sertraline (Shihabuddin and Rapport, 1994) and paroxet-ine (Choo, 1993) – have all been reported to cause or exacerbate extrapyramidal reactions. Sedation, which has been reported with all serotonin reuptake inhibitors, appears to be a primary serotonin effect (Cookson, 1993). Insomnia, however, is more common at higher doses, particularly with fluoxetine. A number of sexual side effects have been attributed to serotonin reuptake blockade, including anorgasmia, ejaculatory difficulties and even spontaneous orgasms associated with yawning (Modell, 1989).
Blockade of the 5-HT2-receptors may result in hypotension and ejaculatory disturbances. Antagonism of serotonin receptors may also be responsible for weight gain and carbohydrate craving.
Increases in dopamine resulting from reuptake blockade can have an antiparkinsonian effect. It can also cause psychomotor activa-tion and aggravation of psychosis.
The blockade of dopamine receptors can result in extrapyrami-dal symptoms. These symptoms include cogwheel-type rigidity, tremor, dyskinesia, masked facies and acute dystonia. Prolonged dopamine blockade appears to be responsible for tardive dyski-nesia. Dopamine receptor blockade has also been associated with endocrine changes and sexual dysfunction.
MAO is the main enzyme responsible for the metabolism of monoamines. There are two main types of MAOs, identified as types A and B. Type A is selective for serotonin and norepine-phrine, and accounts for 80% of the MAO in the brain. Type B selectively deaminates phenylethylamine. Both forms oxidize dopamine and tyramine.
Dietary Restrictions The dietary restrictions required when us-ing MAOIs represent the major limitation to widespread use of these effective antidepressants. Nonselective inhibition of MAO prevents the normal hepatic metabolism of tyramine containing foods or sympathomimetic agents. The increased level of tyramine in the circulation stimulates the release of norepinephrine from sympathetic terminals. This sudden increase in norepinephrine is the basis for the “tyramine–cheese” reaction, so named because cheese is the most common source of the tyramine that causes this reaction. In fact, other pressor amines, such as levodopa, can also cause the reaction, but tyramine – a natural product of food fermentation and bacterial decarboxylation – is the most common in foods. The result of a tyramine–cheese reaction can be a hy-pertensive crisis. Thus, patients should be well educated as to the foods that must be avoided while using MAOIs. In the past, there has been a tendency towards conservative dietary restrictions, often based on single case reports or indirect analogies. More research and experience have suggested that not all the foods commonly restricted are equally likely to precipitate a reaction (McCabe and Tsuang, 1982). Better compliance is likely if a more reasonable diet is prescribed (as suggested in Table 79.5).
Despite the best of preparation, some patients may err and suffer a hypertensive crisis. This is often experienced as a se-vere, pulsating, occipital headache that then generalizes. It may be alleviated with 10 mg of nifedipine, either oral or sublingual (Golwyn and Sevlie, 1993).
MAOIs can cause an increase in standing systolic blood pressure, absent of tyramine containing foods or sympathomi-metics. Generally, this effect is not clinically significant; however, serious unprovoked hypertensive episodes have been reported
(Lavin et al., 1993), and blood pressure should be monitored for 1 to 2 hours after beginning or increasing an MAOI. Hypoten-sion is also a reported effect of MAO, but the mechanism is not known. MAO inhibition can also cause sedation or overstimula-tion. Once again, the mechanism of this is not well understood.
TCAs have effects on cardiac conduction that are independent of anticholinergic or noradrenergic effects. Destabilization of the cardiac membrane can cause dysrhythmia and asystole, particu-larly in overdose.
Allergic reactions can occur with any of these agents. Effects in-clude dermatological (rashes, urticaria, photosensitivity, Stevens Johnson syndrome) and hematological (agranulocytosis) sensi-tivities. Several case reports have described a photosensitivity reaction apparently caused by desipramine that results in a blue– gray pigmentation (Narurkar et al., 1993; Steele and Ashby, 1993). Fluoxetine has been associated with bleeding, inflammation (Gunzberger and Martinez, 1992), and, most seriously, a fatal systemic vasculitis. It should be stopped if a rash develops.
In most cases of allergic reactions, the primary treatment is to stop the agent. In one report, granulocyte colony stimulating factor was used successfully to treat severe chlomipramine-as-sociated agranulocytosis (Hunt and Resnick, 1993).
Abnormal liver function tests have been associated with a number of antidepressants, which can be independent of dose. The risk for such effects may be worsened by chronic alcohol or anticonvulsant use.
A preexisting seizure disorder increases an antidepressant’s likelihood of precipitating a seizure. Other predisposing factors include a family history of a seizure; an abnormal pretreatment electroencephalogram; brain damage; previous electroconvul-sive treatment; abuse or withdrawal from sedatives; alcohol, or cocaine; and concurrent use of CNS-activating medications (Rosenstein et al., 1993). Seizures may be more likely to occur early in treatment, or after a large escalation in dose.
The risk of seizure with TCAs is usually reported as 0.1–1.1%. In unselected populations the risk may be as high as 2 to 2.5% (Davidson 1989). Serotonin reuptake inhibitors appear to have a lower incidence of seizures. Bupropion has a high rate of seizures in patients with a preexisting seizure history, and in patients with bulimia. In patients without these predisposing factors, the risk appears to be about 0.4%; thus, it may have a two- to fourfold risk of seizures compared with other antidepressants. Bupropion’s effect on the sei-zure threshold has never been directly compared with other antidepressants.
Antidepressants have been associated with the precipitation of mania, and rapid cycling bipolar disorder. This appears to be most common in patients with a preexisting history of mania and in unipolar depression the rate of antidepressant-induced mania is very low (,1%). The problem has been most frequently re-ported in TCAs, but has been seen in SSRIs as well (Cookson, 1993). A similar problem has been found with newer agents, in-cluding nefazodone and venlafaxine, though the data for this is more limited. Bupropion may have a lower incidence of mania (Shopsin, 1983).
A variety of sexual side effects can be caused by antidepressants, and they can affect all aspects of sexual response. Thus, anti-depressants can decrease libido, increase impotence and anor-gasmia, and cause delayed or retrograde ejaculation (Segraves, 1992).
SSRIs have a high incidence of delayed orgasm or anor-gasmia. Sexual side effects can occur at even low therapeutic doses, and dose reduction may not be possible. A change of agent may be the only alternative. Bupropion appears to have the lowest incidence of sexual side effects among the antide-pressants, often not differing from placebo in studies of sexual functioning.
Trazodone has been associated with penile priapism; the risk is around 1 in 6000 to 8000 men. Although rare, it is nota-ble that a third of these cases required surgical intervention, and some resulted in permanent impairment. Clitoral priapism has been reported as well (Pescatori et al., 1993).
Occasionally antidepressants can enhance sexual func-tion. This is usually due to the alleviation of depression; however, there have been case reports of improved libido or potency after initiation of an antidepressant, which occurred independent of any antidepressant effect (Smith and Levitte, 1993).
Fine tremors have been noticed with both TCAs and serotonin reuptake inhibitors. The syndrome of inappropriate secretion of antidiuretic hormone has been seen with fluoxetine, as well as with a number of other antidepressants.
Drug interactions are summarized in Table 79.4.
As with any combination therapy, the side effects described previously can be additive with other similar drugs. Most problematical are the anticholinergic effects of the TCAs. Such cholinergic – particularly muscarinic – blockade is a property shared by many other medications, including numerous over-the-counter preparations. The general sedative properties of these medications can also augment any soporific. The slow-ing of cardiac conduction can also potentiate other medications that produce similar effects, such as type IA antiarrhythmics and anticholinergic medications. Adrenergic receptor blockade can worsen the orthostatic hypotension caused by other medi-cations, including vasodilators and low-potency antipsychotic medications.
Absorption of TCAs can be inhibited by cholestyramine, which therefore must be given at different time intervals than the antidepressants. TCA levels can be raised by substances that inhibit enzyme activity, and lowered by substances that induce it. Specific substances reported to increase TCA levels include fluoxetine, antipsychotic medications, methylphenidate and ci-metidine. In a controlled trial, methylphenidate was combined with desipramine to treat attention deficits and depression in children. Enzyme “inducers” that can lower tricyclic agent lev-els include phenobarbital and carbamazepine. The nicotine from cigarettes can also induce enzyme activity.
Guanethidine is contraindicated with TCAs, as it relies on neuronal reuptake for its antihypertensive effect. Clonidine,
presynaptic alpha-2-receptor noradrenergic agonist, is also contraindicated, as it works in an antithetical fashion to tricyclic medications.
As with the dietary proscriptions, any medication that increases tyramine can precipitate a hypertensive crisis. Such medications include numerous over-the-counter preparations for coughs, colds and allergies. The same rule applies to sympathomimetic drugs (such as epinephrine and amphetamines) and dopaminer-gic drugs (such as anti-Parkinsonian medications).
The combination of MAOIs and narcotics – particularly meperidine – may cause a fatal interaction. The reaction can vary from symptoms of agitation and hyperpyrexia to cardiovas-cular collapse, coma and death. The mechanism of this reaction is poorly understood. A similar reaction has also been reported when propoxyphene, diphenoxylate hydrochloride and atropine are used with MAOIs.
The combination of an MAOI with a potentiator of serot-onin (such as a serotonin reuptake inhibitor) can cause the serot-onin syndrome.
Similar to the dietary restrictions, some of the drug re-strictions associated with MAOIs are based on few actual data. Best established are the restrictions against the combination of MAOIs with amines, meperidine, dextromethorphan, hypogly-cemic agents, l-dopa, reserpine, tetrabenazine and tryptophan. TCAs are frequently included on this list as causing a “central excitatory syndrome” in combination with MAOIs, although the two have been combined safely. Blackwell (1991) published a comprehensive review of MAOI drug interactions.
Serotonin reuptake inhibitors are potent inhibitors of the CYP2D6 pathway, and the drug–drug interactions that can result from this have been the subject of a number of books and articles.
Serotonin reuptake inhibitors can slow the metabolism of any drug that is also metabolized by the same cytochrome P450 pathway. Such drugs include TCAs, carbamazepine, phenothi-azines, butyrophenones, opiates, diazepam, alprazolam, vera-pamil, diltiazem, cimetidine and bupropion. Paroxetine appears to be the most potent inhibitor of this metabolic pathway, with fluoxetine also showing high potency. Sertraline is a somewhat less potent inhibitor.
These pharmacokinetic interactions are best managed with dosage adjustment. Fluoxetine, for example, can be safely used with tricyclic medications if TCA blood levels and, possibly, elec-trocardiograms are monitored. In the case of bupropion, this rela-tive increase in the blood level can increase the risk for seizures.
Particular caution should be used when a patient using multiple medications starts a serotonin reuptake inhibitor, as the interactions with other drugs can cause dangerous increases in levels. For example, in the cardiac patient, levels of warfa-rin should be monitored as fluoxetine has been reported to raise these levels (Woolfrey et al., 1993). Several case reports exist of increased antiarrhythmic levels after introduction of fluoxetine, which resulted in potential serious bradyarrhythmias.
Fluoxetine has also been reported to raise lithium levels. The mechanism for this is not clear, as lithium is primarily ex-creted through the kidneys.
Of particular concern is the serotonin syndrome. This syndrome occurs when a serotonin reuptake inhibitor is combined with an-other drug that can potentiate serotonin, such as MAOIs, penta-zocine and l-tryptophan. It has also been reported with the ad-junctive use of less obvious serotonergic drugs, such as lithium (Muly et al., 1993) and carbamazepine (Dursun et al., 1993). This creates a toxic effect with symptoms of abdominal pain, diarrhea, diaphoresis, hyperpyrexia, tachycardia, hypertension, myoclonus, irritability, agitation, epileptic seizures and delirium. In its severest form, it can result in coma, cardiovascular shock and death. For this reason, a clearance period is required before switching between a serotonin reuptake inhibitor and an MAOI. Switching from fluoxetine to an MAOI is particularly difficult, given fluoxetine’s long clearance time – about 6 weeks. Clear-ance is considerably more rapid for sertraline or paroxetine, and a 2-week “wash-out” period is advised when changing from one of these agents to an MAOI. Occasionally, case reports have sug-gested that some patients tolerate a quicker switch; however, a full waiting period remains the most prudent course, as several deaths have occurred after an MAOI was begun too soon after fluoxetine was discontinued (Beasley et al., 1993).
Few reports exist of interactions with other drugs and trazodone, although trazodone may increase levels of digoxin, phenytoin and possibly warfarin. Bupropion causes few drug–drug interactions. The main interactions reported have occurred when bupropion is combined with another dopaminergic agent. For example, when bu-propion was used with l-dopa, the combination caused excitement, restlessness, nausea, vomiting and tremor (Goetz et al., 1984).
Venlafaxine does not substantially inhibit the CYP enzyme, and is not highly protein-bound, thus it tends to have few clini-cally significant drug–drug interactions. Nefazodone is highly protein-bound, and has several active metabolites. It is also a strong inhibitor of CYP3A4, and affects other drugs also me-tabolized by that pathway; however, it has little affinity for the CYP2D6 enzyme. Mirtazapine is highly protein-bound as well, but appears only weakly to affect the cytochrome enzymes.