Once the choice of an antidepressant has been made, the main goal is to maximize therapeutic effects and minimize side effects. Good preparation and reassurance of the patient is essential. Even relatively benign side effects are a major cause of treatment nonadherence; drop-out rates ranging from 7 to 44% have been reported in various studies of tricyclic antidepressants (TCAs), and from 7 to 23% in studies of serotonin reuptake inhibitors. Common side effects for TCAs and selective serotonin reuptake inhibitors (SSRIs) are shown in Table: SSRI, SNRI and TCA Side Effects.

Table: SSRI, SNRI and TCA Side Effects

Anticholinergic Effects

Common side effects include dry mouth, constipation, urinary retention, blurred vision, and less commonly narrow-angle glaucoma. These effects are usually dose-related and worse in patients with pre-existing defects.

Dry mouth can be alleviated by saliva substitutes or sugar-free hard candy, over-the-counter bulk-forming laxatives can treat the constipation caused by some agents, and the cholinergic agonist bethanechol has been used to treat anticholinergic side effects, particularly urinary hesitancy and blurred vision. The usual adult dosage is 10 to 50 mg t.i.d. or q.i.d. Pilocarpine eye drops can also be used to treat blurred vision. Selective serotonin reuptake inhibitors (SSRIs) in general are free from these side effects, as is bupro-prion, although duloxetine and paroxetine may cause mild dry mouth and constipation.

Other effects include tachycardia, impaired memory and cognition (in severe cases leading to delirium), and exacerbation of texisting tardive dyskinesia.

Rarely, in combination with other anticholinergic drugs, tricyclic antidepressants (TCAs) can precipitate a central anticholinergic delirium and confusion. Patients with psychotic depression may be at higher risk as their treatment regimen may include a TCA, a low-potency antipsychotic, and an antiparkinsonism agent. If this syndrome is suspected, a physostigmine challenge can be diagnostic and may produce a dramatic reversal. Abrupt withdrawal of TCAs can put patients at risk of cholinergic rebound. This syndrome includes gastrointestinal distress, anxiety, and autonomic instability. Whenever possible, TCA doses should first be slowly tapered and then discontinued.

Autonomic Effects

The most frequent and treatment-limiting side effect of tricyclic antidepressants (TCAs) is orthostatic hypotension. The geriatric population is especially vulnerable to falls; patients should be educated in how to change position safely. Newer TCAs such as nortripty-line and doxepin have a lower risk of this side effect. Trazodone has significant etj-adrenergic blockade and as a result also induces significant orthostatic hypotension.

Both selective serotonin reuptake inhibitors (SSRIs) and TCAs may also cause sweating, palpitations, and increased blood pressure. Venlafaxine and duloxe-tine also cause sweating and tremor, and slightly increase blood pressure and heart rate; increases in blood pressure are most notable in doses of venlafaxine above 300 mg/day.

Neurologic Effects

Several tricyclic antidepressants (TCAs) may lower the threshold for epileptic seizures, although as a class they have relatively low risk for inducing seizures. Initial doses of TCAs should be reduced in epileptic patients. Some selective serotonin reuptake inhibitors (SSRIs) may increase the frequency of seizures at high dose, particularly fluoxetine at doses of 100 mg/day or more. Buproprion is the agent most likely to reduce the seizure threshold. In doses below 450 mg/d, the incidence of seizures is less than 0.5%. To avoid inducing a seizure, one should give bupropion in divided doses, with a maximum dose of 450 mg/d (400 mg/d for the extended release formulation). Seizure risk is likely to be lower with sustained or extended release forms of buproprion.

Myoclonic twitches and tremor of the tongue and upper limbs can occur in 5-10% of patients on SSRIs and less frequently with tricyclic antidepressants; this may respond to dose reduction or the addition of a low-dose beta blocker such as propranolol. Anxiety, nervousness, insomnia, and sedation may also occur with SSRI agents; these symptoms may respond to a dose reduction or to the short-term addition of a low-dose benzodiazepine. Insomnia is often already part of the depression; the addition of a low-dose of a sedating antidepressant such as trazodone, or a sedative-hypnotic, may allieviate symptoms in the short term. It is more common with high doses of fluoxetine. Headache may also occur with fluoxetine.

More rarely, paresthesia, ataxia, and speech blockade may occur with both TCAs and selective serotonin reuptake inhibitors (SSRIs).

There is some question as to whether SSRIs can induce extrapyramidal-like symptoms, specifically akathisia. It remains unclear whether this is actually an extrapyramidal effect or part of the agitation and anxiety that these agents can produce. The TCA amoxapine can cause extrapyramidal side effects including acute dystonic reactions, parkinsonism symptoms, akathisia, tardive dyskinesia, and neuroleptic malignant syndrome. If akathisia is suspected, dosage reduction may be required.

Weight Gain

Both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) cause weight gain; up to 30% of patients on SSRIs experience this side effect, with increases of 8 kg or more. This is less of a concern during the acute phase of treatment, when insomnia and anorexia are often present, but they can be treatment limiting when long-term use is indicated. Medication switches to less weight-increasing medication may be helpful.

Gastrointestinal Symptoms

Nausea, vomiting, anorexia, and diarrhea are frequent complaints with selective serotonin reuptake inhibitors (SSRIs). They are often dose and titration dependent and can be lessened by dose reduction, a slower initial titration, and having the patient take medications with food. Anorexia usually occurs only early in treatment and is not persistent. Side effects and treatment discontinuation during the early days of treatment associated with paroxetine may be reduced by prescribing the modified-release formulation Paxil CR. Compared with immediate-release tablets, this formulation significantly reduces the incidence of nausea during the first week of therapy. The most frequent adverse effect associated with both venlafaxine and duloxetine is nausea.

Sexual Dysfunction

Every class of antidepressants is associated with some degree of sexual dysfunction. Difficulties can include problems with libido, impotence, ejaculatory dysfunction, and anorgasmy. The incidence of sexual dysfunction is as high as 30% with selective serotonin reuptake inhibitors (SSRIs). As with other side effects, some of these may be symptoms of the depression itself, and they may predate the initiation of the antidepressant trial. Treatment can include dose reduction, skipping of a dose of an SSRI with a short half-life (e.g., sertraline), or changing to an antidepressant of a different class. Anorgasmia may be treated by the addition of yohimbine or amantadine or by the use of bethanechol or cyproheptadine one to two hours before sexual activity. Decreased libido may be treated by the addition of the antidepressant bupropion; in general, this agent has the best profile with respect to sexual dysfunction. Trazodone has been associated with priapism in rare cases; this must be treated urgently to avoid long-term impairment.

Cardiac Conduction

Tricyclic antidepressants (TCAs) affect cardiac conduction; as a result, they have antiarrhythmic properties and can slow cardiac conduction. These effects are responsible for the cardiotoxicity of TCAs and their danger in overdose. TCAs do not affect cardiac output, however they should not be used in patients with a preexisting conduction delay greater than a first-degree block or in patients immediately after myocardial infarction.

Suicide Risk

Selective serotonin reuptake inhibitors (SSRIs) have a very wide therapeutic index and are not lethal in overdose. This has made them especially popular in the treatment of patients with a history of impulsivity. The possibility that treatment with any type of antidepressant may increase the risk of suicide in adults is currently under active review. It is clinically prudent to limit the amount prescribed during the initiation of therapy or when patients are only partially treated. The risk of suicide attempts during these intervals is high. More than a 1-week supply of a TCA is potentially lethal in an overdose attempt.

Pooled analysis of clinical trials involving children and adolescents suggests that antidepressants are associated with suicidal thinking or behavior in about 4% of patients compared with 2% receiving placebo during the early months of treatment.

All patients treated with an antidepressant (adults as well as children and adolescents) should therefore be closely monitored during the first few months. Treatment may need to be adjusted or discontinued if depression continues to worsen or suicidal ideation emerges, especially if the symptoms are severe, abrupt in onset, or not part of the patient’s presenting symptoms. Patients should be warned of this possibility and provided with information about the risk and advice on what precautions to take. They should be warned to report new or increased signs of irritability, agitation, or suicidality to a healthcare professional.

Allergic and Hematologic Effects

Tricyclic antidepressants (TCAs) are associated with exanthematous rashes in 4-5% of patients, while selective serotonin reuptake inhibitors (SSRIs) have been known to cause a variety of rashes in a similar percentage of patients.

Other Effects

TCA’s can cause gynecomastia and amenorrhea in some patients, while selective serotonin reuptake inhibitors (SSRIs) can cause increased prolactin levels causing mammoplasia and galactorrhea in both men and women. SSRIs have also been known to reduce blood glucose levels, though this is rare. Nefazodone has been associated with rare cases of life-threatening liver failure, and has been removed from the market in many European countries. As a result, nefazodone should not normally be considered for use before other antidepressants.

Central Serotonergic Syndrome

Any agent that increases serotonergic function can put patients at risk of a central serotonergic syndrome. This syndrome most commonly affects patients on multiple serotonergic drugs, and involves multiple systems. The syndrome can in rare cases progress to rhabdomyolysis, acidosis, respiratory compromise, disseminated intravascular coagulation, and cardiac collapse.

Monoamine Oxidase Inhibitors

The declining popularity of monoamine oxidase inhibitors (MAOIs) in the United States is primarily the result of the need for dietary restrictions and the potential for serious side effects. Use of MAOIs must be limited to patients who are compliant with a tyramine-free diet and do not use any medications that contain sympathomimetic amines. A hypertensive crisis is a potentially fatal, though rare, complication of these drugs. The crisis is usually preceded by a prodrome that includes increased blood pressure, headache, stiff neck, and vomiting. Treatment needs to be immediate and may include the administration of phentolamine, 5 mg i.v.

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