Side Effects of Psychotropic Medications

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) have a number of common side effects that require careful management. Anticholinergic effects (including dry mouth, blurry vision, urinary hesitancy, constipation, tachycardia, and delirium) that result from the blockade of muscarinic cholinergic receptors can occur with use of TCAs. In addition, anticholinergic effects can also be dangerous to patients with pre-existing glaucoma (leading to acute angle-closure glaucoma), benign prostatic hypertrophy (leading to acute urinary retention), and dementia (leading to acute confusional states). TCAs can also cause sedation that results from blockade of H ₁ histamine receptors, and ortho­static hypotension, due to blockade of alpha ₁ receptors on blood vessels. All three of these side-effect clusters are more common with tertiary amine TCAs (e.g., amitriptyline, doxepin, clomipramine, imipramine) than with secondary amine TCAs (e.g., nortriptyline, desipramine, protriptyline). TCAs may also cause increased sweating. Longer-term side effects of TCAs include weight gain (related to histamine receptor blockade) and sexual dysfunction. Box 12-2 describes the management of common side effects of TCAs and other antidepressants.

In addition to these common initial and long-term side effects, TCAs may have more serious but uncommon side effects; many of them are cardiac in nature. These agents are structurally similar to class I antiarrhythmics that are actually pro-arrhythmic in roughly 10% of the population; approximately 20% of patients with pre-existing conduction disturbances have cardiac complications while taking TCAs. TCAs are associated with cardiac conduction disturbances and their use can lead to prolongation of the PR, QRS, and QT intervals on the electrocardiogram (ECG) and have been associated with all manner of heart block. Some have suggested that effects on cardiac conduction are most severe with desipramine, while other studies have found amitriptyline and maprotiline to be most associated with torsades de pointes. Furthermore, these agents have been associated with an increased risk of myocardial infarction (MI) when compared to selective serotonin reuptake inhibitors (SSRIs). In addition to cardiac effects, other serious adverse events include the serotonin syndrome that occurs most often when TCAs are combined with other serotonergic agents, especially monoamine oxidase inhibitors (MAOIs). This syndrome can include confusion, agitation, and neuromuscular excitability (including seizures).

Adverse effects associated with TCA overdose include the exacerbation of standard side effects (e.g., severe sedation, hypotension, anticholinergic delirium). Ventricular arrhythmias and seizures can also result from TCA overdose. TCA overdose is frequently lethal, with death most often occurring via cardiovascular effects. Figure 12-1 shows an ECG (with characteristic QRS interval widening) of a patient following TCA overdose. A withdrawal syndrome (manifested by malaise, nausea, muscle aches, chills, diaphoresis, and anxiety) can occur following abrupt discontinuation of TCAs; the syndrome is thought to result from cholinergic rebound.

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are generally well tolerated. The most common side effects of SSRIs include gastrointestinal side effects (e.g., nausea, diarrhea, heartburn) that likely result from interactions with serotonin receptors (primarily 5-HT ₃ that line the gut), central nervous system (CNS) activation (e.g., anxiety, restlessness, tremor, insomnia), and sedation that appear within the first few days of treatment. Gastrointestinal side effects may be most common with sertraline and fluvoxamine, CNS activation with fluoxe­tine, and sedation with paroxetine. Headache and dizziness can also occur early in treatment. These symptoms often improve or resolve within the first few weeks of treatment. Rarely, akathisia or other extrapyramidal symptoms (EPS) may occur (sertraline appears to be the most frequent offender due to its dopamine-blocking properties). Nausea, insomnia, and somnolence are adverse effects that most often lead to dis­continuation of SSRIs. It is notable that the rate of discontinuation due to side effects is higher with fluvoxamine than with other SSRIs.

Longer-term side effects associated with SSRIs include sexual dysfunction, which occurs in 30% or more of SSRI-treated patients; SSRI-induced sexual dysfunction occurs in both men and women, affecting both libido and orgasms. Weight gain, fatigue, and apathy are infrequent long-term side effects; weight gain may occur more frequently with paroxe­tine. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can occur with all SSRIs, though it may be more frequent with fluoxetine. Finally, SSRIs may increase the risk of bleeding, primarily due to the effects of these agents on serotonin receptors of platelets, resulting in decreased platelet activation and aggregation; it appears that the bleeding risk associated with use of SSRIs is similar to that of low-dose non-steroidal anti-inflammatory agents. SSRIs are relatively safe in overdose. The serotonin syndrome can occur when these agents are combined with other serotonergic compounds, or, very rarely, when used alone.

SSRIs are generally considered safe in terms of cardiovascular side effects. Recently, concern has arisen regarding the possibility of SSRIs leading to prolongation of the QTc interval and increasing the risk for torsades de pointes, a potentially lethal ventricular arrhythmia. In fact, all SSRIs have been associated in case reports with QTc prolongation at therapeutic doses and in overdose. In particular, citalopram has been shown to have a modest QT-prolonging effect, which resulted in a recommendation from the Food and Drug Administration (FDA) in August 2011 to limit the maximum daily dose of citalopram to 40 mg (20 mg in patients with hepatic impairment or those older than 60 years) because of the increased risk of QTc prolongation at higher doses, and to declare its use contraindicated in patients with congenital long-QT syndrome. Less stringent recommendations were issued in March 2012, but citalopram remains not recommended for use at doses greater than 40 mg per day. No QTc-related recommendations have been issued for other SSRIs, though escitalopram appears to have a more modest, dose-dependent effect on prolongation of the QTc interval.

Finally, abrupt withdrawal from SSRIs can lead to a withdrawal syndrome characterized by several somatic symptoms. The syndrome includes disequilibrium (dizziness, vertigo, and ataxia), flu-like symptoms (headache, lethargy, myalgias, rhinorrhea, and chills), gastrointestinal symptoms (nausea, vomiting, and diarrhea), sensory disturbances (paresthesias and sensations of electrical shock), and sleep disturbances (insomnia, fragmented sleep, and vivid, often frightening, dreams). In addition, a number of psychological symptoms (e.g., agitation, irritability, anxiety, crying spells) are associated with SSRI discontinuation.

Symptoms of the discontinuation syndrome typically begin 1 to 3 days after withdrawal of an SSRI, though when associated with a longer–half-life agent (fluoxetine in particular), symptoms may begin as long as 7 to 10 days after its discontinuation. Symptoms usually resolve within 2 weeks. If the original antidepressant is restarted, or another SSRI is substituted, the symptoms resolve, usually within 24 hours of re-initiation. This syndrome is most common with SSRIs with shorter half-lives (paroxetine and fluvoxamine); it rarely occurs with fluoxetine, whose metabolite has a half-life of more than 1 week. The syndrome is thought to result from diminished synaptic serotonin levels at serotonin receptors that have been desensitized in the context of serotonin reuptake inhibition.

Serotonin-Norepinephrine Reuptake Inhibitors

Monoamine Oxidase Inhibitors

Tranylcypromine and phenelzine are the most commonly used oral MAOIs and are both irreversible inhibitors. Tranylcypromine is associated with anxiety, restlessness, insomnia, and tremor, while phenelzine is more associated with sedation, mild anticholinergic effects, and orthostatic hypotension (though this last effect can occur with both agents). Both agents are associated with headache, dry mouth, and gastrointestinal side effects. With regard to long-term side effects, weight gain and sexual dysfunction can occur with all MAOIs, though perhaps more commonly with phenelzine. MAOIs can result in symptoms of pyridoxine deficiency, including paresthesias and weakness. Finally, MAOIs have been associated with elevated liver transaminases, though true hepatotoxicity is exceedingly rare.

Hyperadrenergic crises, characterized by occipital headache, nausea, vomiting, diaphoresis, tachycardia, and severe hypertension, can occur in patients taking MAOIs. These most commonly occur when tyramine-containing foods are consumed or when adrenergic agonists (such as sympathomimetics) are taken in combination with MAOIs. Box 12-3 lists tyramine-containing foods that should be avoided by patients on MAOIs. Serotonin syndrome can also occur with MAOIs when these agents are taken with SSRIs, TCAs, or other serotonergic agents ( Box 12-4 lists medications that should be avoided by patients taking MAOIs). MAOI overdose is quite dangerous, with rates of death higher than those for SSRIs and other newer antidepressants ; with serotonin syndrome, neuromuscular excitability, seizures, arrhythmias, and cardiovascular collapse are all possible.

The transdermal MAOI (selegiline) patch does not require dietary modification at its lowest dose. At this lowest dose (6 mg/24 hours) transdermal selegiline appears to have an incidence of orthostatic hypotension, gastrointestinal side effects, weight gain, and sexual dysfunction that is greater than placebo, but lower than with orally-ingested MAOIs; skin irritation at the patch sites has been the most common adverse effect. At doses above 6 mg/24 hours, dietary modification is required, and at all doses concomitant medications that increase catecholamines or serotonin should be avoided as with the oral MAOIs.

Other Antidepressants

Lithium

Lithium has many associated adverse effects, summarized in Box 12-5 . Gastrointestinal and neurological side effects (e.g., sedation, tremor), along with increased thirst, often occur early in therapy, while effects on thyroid and renal function occur more chronically. Box 12-6 summarizes potential treatments for lithium-induced side effects; change in dosing and formulation can reduce gastrointestinal side effects, while other side effects require additional therapies. Lithium has some effects on sino-atrial node transmission and (less commonly) an atrio-ventricular conduction. However, it has not been commonly associated with other effects on the cardiovascular system, and cardiac disease (aside from sick sinus syndrome) is not an absolute contraindication for lithium use. Lithium has a low therapeutic index and lithium toxicity (whether intentional or unintentional) can lead to a variety of symptoms, including neurological (e.g., severe sedation, tremor, dysarthria, delirium, anterograde amnesia, myoclonus, seizure), gastrointestinal (e.g., nausea, vomiting), and cardiovascular (e.g., arrhythmia) effects; renal function often is impaired, and dialysis may be required to treat lithium toxicity if supportive measures and intravenous (IV) normal saline to aid lithium excretion are ineffective. Lithium does not have a characteristic discontinuation syndrome, but rapid withdrawal of lithium therapy is associated with substantially higher rates of relapse than when lithium is tapered.