Perioperative Considerations for Patients with Major Depressive Disorder Undergoing Surgery

Abstract

In the United States, about 15 percent of adults suffer from major depressive disorder (MDD), which results in an annual cost of over $200 billion per year. In the perioperative setting, MDD is associated with increased morbidity and mortality. While the exact causes of the increase in adverse outcomes are unknown, decades of research have shown that depression affects virtually all major systems in the human body. As a result, antidepressants are among the most frequently prescribed medications in the United States. The pharmacological action of most anti-depressants assumes that depression results from a deficiency of dopamine, norepinephrine, and serotonin or alterations in their target receptors. Unfortunately, anesthesia and medications used in the perioperative period affect the same neurotransmitters. As a result, patients with MDD are at an increased risk for hypotension, cardiac arrhythmias, acute hypertension, altered thermoregulation, and postoperative cognitive dysfunction. Given the increasing rate of MDD and antidepressant utilization, anesthesia providers and perioperative nurses must understand the pharmacological action of antidepressants to decide when to continue or hold antidepressants preoperatively and avoid potential drug interactions. This article reviews the pathophysiology of MDD, mechanism of action of antidepressants, and perioperative considerations for patients on antidepressant medications.

Introduction

Major depressive disorder (MDD) is a common and treatable mental disorder that is the leading cause of disability worldwide.¹ It affects more than 300 million people worldwide,¹ and about 15 percent of adults in the United States.² In the United States, the economic impact of depression is substantial; it costs over $210 billion annually.³ The high financial costs associated with MDD can partly be attributed to decreased work productivity, decreased quality of life, and difficulties performing tasks at work and home.⁴ MDD has also been associated with increased postoperative morbidity and mortality for patients undergoing various surgical procedures.^5–8

Many patients presenting for surgery have a diagnosis of depression and may be taking antidepressant medications. Anesthesia providers and perioperative nurses have a significant role in taking care of these patients. Providing care to these patients comes with multiple challenges. For instance, both commonly used antidepressants such as tricyclic antidepressants (TCAs) and anesthesia medications such as ketamine alter the transmission of neurotransmitters in the brain.^9,10 The interaction between depression, antidepressants, and medications used during the perioperative period have been associated with arrhythmias,¹¹ hypotension,¹² persistent postoperative pain, and postoperative cognitive dysfunction.^13,14 Unfortunately, when patients present for surgery (especially during emergency procedures) depression and other psychiatric disorders may not be at the forefront of clinical care decisions.

This article aimed to review the perioperative management of patients with depression. To achieve this goal, first, we discussed recent advances in the understanding of the pathophysiology of depression. Second, we examined the mechanism of action of antidepressant medications. Finally, we presented potential interactions between antidepressants and medications used in the perioperative period with implications for clinical practice.

Overview of Major Depressive Disorder

Despite the fact that major depressive disorder affects virtually every system in the human body, the exact etiology and pathophysiology remain unknown.¹⁵ However, two prominent theories explain our current understanding and treatment of depression.¹⁵ The first and predominant theory suggests that depression results from a deficiency or imbalance of monoamines in the central nervous system.¹⁶ The second theory postulates that dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) through neuroinflammatory mediators that modulate the body’s response to stress plays a role in depression.¹⁵ Recent studies have shown that genetic and epigenetic modifications also play a role in depression.^15–17 A description of the role of genetic and epigenetic changes on MDD is beyond the scope of this paper.

Neuroanatomical findings from over 30 years ago reported that serotonin, norepinephrine, and dopamine secreted by nerve terminals in the brain regulate mood, attention, cognition, appetite, sleep, and reward processing.^15,18,19 Thus, the monoamine hypothesis of depression proposes that a functional deficiency of these neurochemicals or alterations in their receptors play a critical role in major depressive disorders.¹⁶ Functional neuroimaging studies have associated depressive symptoms with reductions in monoamines.²⁰ For instance, deficiencies of serotonin levels have been associated with depressive symptoms including aggressive behavior, suicidal ideations, and impulsivity.²¹ Similarly, derangement of dopamine levels have been associated with anhedonia, psychomotor retardation, hypersomnia, inattention, and pseudodementia.²² Today, most of the commonly administered antidepressants (SSRIs, TCAs, MAOIs, and atypical antidepressants) alleviate depressive symptoms by increasing the levels of these neurotransmitters. Despite the clinical effectiveness of these medications, the monoamine hypothesis of depression remains questionable.²³

Inflammatory cytokines play an essential role in brain development, neuroplasticity, immune function, adaptation to stress, neurogenesis, and behavior.²⁴ The course of major depression closely mimics an inflammatory response, and clinical studies have shown that patients with major depression have elevated levels of proinflammatory cytokines.²⁴ A meta-analysis found that patients with major depression have higher levels of proinflammatory markers (interleukin 1beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα)) when compared to a healthy control group.²⁵ Also, acute administration of inflammatory cytokines to animal models and humans has been associated with depressive symptoms.²⁶ Although the physiological mechanisms remain relatively unclear, an increase in proinflammatory cytokines is believed to be associated with a disruption in neuronal plasticity with subsequent neurodegeneration, damage to glial cells, and inhibition of growth factor activity that prevents neurogenesis and promotes depressive symptoms.^16,26

Exposure to psychosocial stress promotes neuroinflammation and is associated with the development of depressive symptoms.^15,27 Stress activates the HPA which results in the release of stress hormones (e.g., glucocorticoid, growth hormone, and catecholamines). Stress and associated stress hormones also activate genes that code for inflammatory mediators.²⁷ The body’s response to stress and associated depressive symptoms has direct implications for patient care during the perioperative period because these patients face significant psychological and physical stress. For instance, consider a patient who is undergoing a mastectomy for metastatic breast cancer. The immune system plays a significant role in carcinogenesis and metastasis. The psychological stress of cancer and life-altering surgery, plus the physical stress of surgery triggers the HPA and emotional circuits in the brain with a resultant increase in inflammatory cytokines such as IL-1β, IL-6, and TNF-α.²⁸ It has been suggested that altered immunity and depression increases the risk of malignancy and affects postoperative outcomes.^28,29 As a result, optimal management of their depressive symptoms and antidepressants is essential for optimal perioperative outcomes.

Antidepressants and Perioperative Considerations

Historically, the pharmacological treatment of depression assumes that it is caused by a functional deficit of neurotransmitters or receptor alterations in the serotoninergic, dopaminergic, and norepinephrinergic systems. As a result, antidepressants are used to increase the levels of these neurotransmitters at the synaptic cleft (receptor site) by facilitating their release from the presynaptic vesicles, inhibiting enzymatic breakdown, or preventing their reuptake into the presynaptic terminal. Based on their primary mechanism of action, antidepressants can be classified as SSRIs, TCAs, MAOIs, atypical antidepressants, and lithium.

Selective serotonin reuptake inhibitors (SSRIs)

Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter synthesized from tryptophan and released from the neuron originating from the raphe nuclei in the midbrain, pons, and brainstem.³⁰ It has pre- and postsynaptic 5-HT receptors and affects a variety of systems in the body.^30,31 In the gastrointestinal system serotonin affects motility, secretions, and tone. In the cardiovascular system, it affects vascular tone, while in the central nervous system it regulates pain, body temperature, cerebral function, sleep, addiction, sexuality, appetite, emotion, mood, and response to stress.^30,32 Also, levels of serotonin in the brain have been associated with learning, memory, motivation, and behavioral processes that regulate mood and depression.^31,33 Even though, the causal relationship between serotonin levels and depression remains questionable, SSRIs are effective at alleviating depressive symptoms.^23,31

SSRIs are the most commonly used antidepressants in the United States because of their relatively high margin of safety.³⁴ Examples of SSRIs include citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). Despite the variability in their chemical structure, all SSRIs decrease the presynaptic reuptake of serotonin. This increases the availability of serotonin in the synapse and increases the amount of serotonin bound to the postsynaptic receptors. Also, several studies have shown that SSRIs modulate the effects of inflammatory cytokines by decreasing the levels of proinflammatory markers such as IL-6, TNF-α, and IL-1β.³⁵

Perioperative consideration for a patient on SSRIs

Patients should continue SSRIs throughout the perioperative period to avoid discontinuation syndrome. Discontinuation syndrome refers to a group of symptoms experienced by a patient following the abrupt discontinuation of an SSRI.³⁶ These symptoms usually develop 1 to 7 days following the discontinuation of the SSRI and include dizziness, lethargy, sleep disturbances, anxiety, confusion, headache, tremor, visual changes, delirium, hallucination, and myalgia among others.³⁷ In the postoperative period, discontinuation syndrome may be confused with postoperative cognitive dysfunction, drug withdrawal, atropine anticholinergic crisis, or postoperative pain.³⁸ Also, patients experiencing discontinuation syndrome may injure themselves or the provider. As a result, a thorough and careful exploration of the medication history is required for an appropriate diagnosis. Once diagnosed the symptoms can be managed by patient education, reassurance, and administration of the SSRI.³⁷

Some SSRIs inhibit the cytochrome P450 2D6 enzyme which metabolizes many drugs used in the perioperative period. This enzyme inhibition increases the plasma level of drugs such as benzodiazepines, barbiturates, beta-adrenergic receptor blockers, and antiarrhythmics. Inhibition of this enzyme can also reduce the conversion of prodrugs such as tramadol, codeine, and oxycodone into their active metabolite O-desmethyltramadol, morphine, and oxymorphone respectively. Consequently, this reduces the analgesic effect of some of these drugs.

SSRIs may be associated with an increased risk for bleeding, especially when co-administered with non-steroidal anti-inflammatory drugs (NSAIDs).^39,40 A meta-analysis of over 400 papers found that SSRIs are associated with a higher risk of bleeding and red blood cell transfusion in patients undergoing coronary artery bypass graft surgery.⁴⁰ The increased risk of bleeding has also been reported in non-cardiac surgical procedures such as breast cancer surgery.⁴¹ Thus, hemorrhage and postoperative bleeding should be closely monitored on patients taking SSRIs. Caution must be used when administering NSAIDs for pain control.

Concurrent administration of SSRIs and some perioperative medications is associated with a rare but life-threatening neurological complication known as serotonin syndrome. Commonly used perioperative medications that can increase the risk for serotonin syndrome include fentanyl, tramadol, meperidine, methadone, ondansetron, metoclopramide, and granisetron. Serotonin syndrome is caused by increased serotonin levels in the central nervous system. It is characterized by altered mental status, neuromuscular hyperactivity (tremor, clonus, hypertonia), and autonomic instability (diaphoresis). Diagnosis in the perioperative period can be challenging because of the wide variability in clinical presentation and the fact that it can mimic other perioperative complications such as shivering, seizures, neuroleptic malignant syndrome, and malignant hyperthermia (Table 1).^42,43 There is no gold standard for diagnosis of serotonin syndrome, instead differential diagnoses depend primarily on criteria developed by Hunter, Sternbach, and Radomski.⁴⁴ Of these three criteria, Hunter’s criteria are most sensitive and specific.⁴⁵ Hyperthermia (temperature >41.1°C), rigidity and hypertonicity are standard features of serotonin syndrome.⁴⁴ Irrespective of the symptoms, management primarily consists of cessation of the triggering agent and supportive care. Supportive care includes management of symptoms and hemodynamic stabilization: cardiac monitoring for autonomic instability, intravenous fluid administration, beta blockers for tachyarrhythmia, and benzodiazepines such as midazolam for agitation and tremors. Severe cases can be managed with hypothermia, neuromuscular blocking agents, tracheal intubation, and sedation.

Table 1.

Differential Diagnosis of Serotonin Syndrome

	Serotonin Syndrome	Neuroleptic Malignant Syndrome	Malignant Hyperthermia
Triggering agents	MAOIs, SSRIs, TCAs, SNRIs, amphetamines, serotonin antagonists, St. John’s Wort	Atypical antipsychotics, Typical antipsychotics, or dopamine antagonist	Volatile anesthetics or depolarizing neuromuscular blocking agent
Clinical Presentation	Hyperthermia (temperature >41.1°C suggest a severe case), progressive respiratory failure, altered mental status(agitation, akathisia, confusion), peripheral (especially lower extremities) hypertonicity, truncal rigidity, clonus, hyperreflexia Hunter’s Diagnostic Criteria Use of serotonergic agent and 1 of the following: • spontaneous clonus, • inducible clonus plus agitation or diaphoresis, • ocular clonus plus agitation or diaphoresis, • tremor and hyperreflexia, hypertonia • temperature above 38°C plus ocular or inducible clonus	Labile blood pressure, hyperventilation, tachycardia, hyperthermia, skin pallor, muscle rigidity, tremor, chorea, akinesia, dystonic movement, autonomic instability, seizures, mutism, abnormal reflexes, metabolic acidosis, elevated creatinine phosphokinase, rhabdomyolysis, leukocytosis, renal failure, sialorrhea	Early: Tachycardia, hyperventilation, a rapid increase in end-tidal CO2, hypoxia, hypertension (early), masseter spasm, generalized muscular rigidity, Late: hyperthermia, rhabdomyolysis, metabolic acidosis, acute renal failure, hyperkalemia, increased creatine phosphokinase, myoglobinuria, hypotension, arrhythmias, circulatory collapse
Treatment	Stop triggering agent, supportive care: cooling, hemodynamic support, benzodiazepines, cardiac monitoring, and prevention of neurological sequelae. Severe cases: Serotonin antagonist (Cyproheptadine and Olanzapine), sedation and paralysis with a non-depolarizing muscle relaxant, admission to a critical care unit	Stop triggering agent, supportive care: aggressive hydration, cooling, hemodynamic management, and prevention of neurologic sequelae. Severe cases: Benzodiazepine (Lorazepam 1 to 2 mg parenterally). Bromocriptine orally or via nasogastric tube (2.5mg 2 or 3 times daily for a hypodopaminergic state), Dantrolene IV (1 to 2.5mg/kg every 6 hours; max. of 10 mg/kg/day). Electroconvulsive therapy (ECT) may be used in refractory catatonic cases.	Stop triggering agent (maintain with non-triggering agents if surgery must continue), notify surgeon, call for help, supportive care: hyperventilate with 100% oxygen, hemodynamic management (avoid calcium channel blockers), hydration (diuresis to >1ml/kg/hr), manage acid-base status, dantrolene IV (2.5–10 mg/kg until decrease in ETCO2), charcoal filters, cool patient to <38°C, treat hyperkalemia, admission to critical care unit

Tricyclic Antidepressants (TCAs)

Before the discovery of SSRIs, TCAs were the most commonly administered antidepressants.⁴⁶ TCAs are secondary and tertiary amines that share a similar chemical structure containing three aromatic (ring) structures. Examples of TCAs include amitriptyline (Elavil), amoxapine (Asendin), desipramine (Norpramin), doxepin (Sinequan), imipramine (Tofranil), nortriptyline (Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil). Unlike SSRIs, TCAs inhibit the reuptake of both serotonin and norepinephrine into the nerve terminal, thus prolonging the actions of these neurotransmitters. Besides, TCAs are potent antihistamines that block histamine-1 receptors. TCAs have also been reported to block acetylcholine at muscarinic receptors, and lower the seizure threshold.⁴⁷

Increased levels of norepinephrine in the brain and spinal cord enhances both its analgesic effects and the antidepressant effects of TCAs.^46,47 As a result, TCAs are frequently administered for the management of postoperative pain and neuropathic pain. This analgesic effect stems from the fact that norepinephrine stimulates α−₂- adrenergic receptors in the spinal cord, which inhibit voltage-gated Ca²⁺ channels and prevents the release of excitatory neurotransmitters.⁴⁷ Inhibition of these neurotransmitters is believed to be effective against neuropathic pain associated with hyperalgesia and allodynia.

Perioperative Considerations for a patient on TCAs

Patients should continue TCAs during the perioperative period to prevent discontinuation syndrome, but caution is required to avoid TCA toxicity when administering a TCA preoperatively for postoperative pain control. Rapid absorption of TCAs from the gastrointestinal tract makes TCA toxicity a relatively common adverse effect. Signs and symptoms of TCA toxicity include seizure, sedation, decreased gastrointestinal motility, delirium, cardiac arrhythmias, hypotension, and cardiac arrest.^46,48 Lidocaine has proved effective at preventing cardiotoxicity, which is the most common cause of mortality.⁴⁸

Given that TCAs inhibit the reuptake of norepinephrine, the increased availability of catecholamines in the central nervous system may increase the anesthetic requirement.⁴⁷ Also, care must be taken to avoid sympathetic stimulation and activities that increase the release of catecholamines. Patients on TCAs may be responsive to sympathetic stimulation such as tracheal intubation and surgical incision. Thus, an adequate dose of opioids (e.g., fentanyl) should be administered before tracheal intubation and surgical incision. Alternatively, a quick-acting adrenergic antagonist (e.g., esmolol) should be readily available to correct any increase in sympathetic activity. Anticholinergic medications (e.g., atropine) that cross the blood-brain barrier are best avoided because they may exacerbate postoperative confusion.⁴⁹ Similarly, 1ghadministration of an indirect-acting sympathomimetic medication (e.g., ephedrine) may cause an exaggerated increase in blood pressure and should be avoided. Histamine-releasing agents (e.g., pancuronium or meperidine), ketamine, and epinephrine containing solutions (e.g., local anesthetics mixed with epinephrine) should be avoided.⁴⁷

Chronic administration of TCAs may be associated with depletion of cardiac catecholamines.⁴⁶ These patients may show an exaggerated response to the cardiac depressant effects of anesthetic medications. Treat hypotension with fluid boluses and direct-acting vasopressors such as phenylephrine. For all patients on TCAs, close monitoring of the ECG for arrhythmias such as T-wave changes, bundle branch blocks, premature ventricular contractions, widening of the QRS complex or prolongation of the QT interval is recommended. Finally, concurrent administration of TCAs and tramadol can result in seizure and serotonergic crisis.⁵⁰

Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) enzymes metabolize neurotransmitters by deamination.⁵¹ The two types of MAO enzymes found throughout the body include MAO-A and MAO-B.⁵¹ The MAO-A enzyme deaminates epinephrine, norepinephrine, and serotonin whereas the MAO-B enzyme deaminates tyrosine and dopamine.⁵¹ The administration of MAOIs results in increased concentrations of these neurotransmitters because MAOIs bind to MAO enzymes and render them pharmacologically inert.⁵² MAOIs result in exaggerated sympathetic responses because of the presence of excess neurotransmitters in synaptic clefts.⁵¹ There are emerging MAOI drugs that are selective MAO inhibitors and have fewer side effects (e.g., pirlindole, toloxatone, and safinamide).⁵³

MAOIs were initially discovered in the 1950s and were the first antidepressant drugs to be used clinically.⁵⁴ Tranylcypromine (Parnate) and phenelzine (Nardil) both bind irreversibly to MAO-A and MAO-B.^51,54 A newer MAOI, moclobemide, selectively and reversibly binds to only MOA-A and results in a decreased occurrence of hypertensive crises because MAO can still metabolize some of the neurotransmitters.^51,54 An Emsam (deprenyl) patch at low doses (6 mg or less) is a selective MAO-B inhibitor that has no dietary restrictions or reported instances of hypertensive crises, although the anesthetic implications are unknown.⁵⁵ The discovery of other classes of antidepressants resulted in a marked decrease in the use of MAOIs because of the propensity for patients to develop hypertensive crises with the ingestion of tyramine-rich (fermented) foods or the administration of indirect acting sympathomimetics.⁵¹ The dietary restrictions for patients on MAOIs include aged cheeses, cured meat, smoked meat, sauces (e.g., soy, shrimp, miso, or teriyaki), soybeans, snow peas, meat tenderizers, yeast-extract, and alcoholic beverages.⁵⁶ Currently, the use of MAOIs are typically limited to patients who have failed to respond to all other antidepressant drug classifications.^51,56

Perioperative Considerations for a Patient on MAOIs

There are currently no evidence-based guidelines or expert consensus statements on whether MAOIs should be discontinued perioperatively.⁵¹ The sudden discontinuation of MAOIs may result in withdrawal symptoms (e.g., irritability, insomnia, nausea, psychosis, or mania) and patient suicide.^51,57 MAOIs are often continued perioperatively to avoid these complications.⁵¹ Decisions to stop MAOI therapy for elective procedures should be made after a thorough discussion between the anesthesia provider, the psychiatric team, and the patient.⁵² Additionally, discontinuing the MAOI will require gradual tapering of the medication dosage over time with immediate re-introduction after the surgical procedure.⁵²

The co-administration of MAOIs and opioids can result in excitatory (type 1) or depressive reactions (type 2).⁵² Dextromethorphan, tramadol, and meperidine should be avoided in patients on MAOIs because they can trigger serotonin syndrome (an excitatory reaction).⁵² All opioids can result in a depressive reaction that is characterized by enhanced sedation, hypotension, respiratory depression, and coma.⁵⁴ Opioid-induced depressive reactions are reversible by naloxone administration.⁵⁴

All indirect-acting sympathomimetics should be avoided in patients on MAOIs because they can illicit fatal hypertensive crises.^51,52,54 The commonly used indirect-acting sympathomimetics in anesthesia include ketamine,⁵⁸ ephedrine,⁵⁹ and pancuronium.⁵² Ketamine is an indirect-acting sympathomimetic that increases the pre-synaptic release of MAO and inhibits pre-synaptic MAO re-uptake.⁵⁸ Ephedrine should be avoided because it is both a direct and indirect-acting sympathomimetic.^51,59 Direct-acting sympathomimetics (epinephrine, norepinephrine, and phenylephrine) will have an exaggerated hemodynamic response but may be used if carefully titrated.^51,54 Hypotension in patients on MAOIs should initially be treated with adequate hydration before the use of direct-acting sympathomimetics.⁵¹

Several drug classes may safely be used during anesthesia. Barbiturates may be used at reduced dosages because MAOIs impair their hepatic metabolism.^52,54 Propofol, etomidate, local anesthetics (use caution with the addition of epinephrine), volatile anesthetic agents, anticholinergic drugs, and non-steroidal anti-inflammatory drugs may be administered to patients on MAOIs.⁵⁴

Atypical Antidepressants

The term atypical antidepressants refer to a broad and diverse collection of newer drug classifications that do not share the same pharmacological activity of previous antidepressants (i.e., SSRIs, tricyclic antidepressants, and MAOIs). Atypical antidepressants include serotonin-norepinephrine reuptake inhibitors (SNRI), norepinephrine-dopamine reuptake inhibitors, serotonin receptor antagonist with serotonin reuptake inhibition, noradrenergic alpha-2 receptor antagonists with 5-HT_2&3 antagonism, atypical antipsychotics, and N-methyl-D-aspartate glutamatergic blockers.^53,60 See Table 2 for a summary of atypical antidepressants with example drugs. There are several other classes of atypical antidepressants that will not be covered in this review because the Food and Drug Administration does not approve them in the United States.⁵³

Table 2.

Summary of Common Atypical Antidepressant Drug Classifications

Drug Classification	Drug Example(s)
Serotonin-norepinephrine reuptake inhibitors (SNRI)	Venlafaxine Desvenlafaxine Duloxetine
Norepinephrine-dopamine reuptake inhibitors	Bupropion
Serotonin receptor antagonist with serotonin reuptake inhibition	Trazadone Nefazodone Vortioxetine
Noradrenergic alpha-2 receptor antagonists with 5-HT2&3 antagonism	Mirtazapine
Atypical antipsychotics	Quetipine Risperidone Lurasidone Aripiprazole
N-methyl-D-aspartate glutamatergic blocker	Ketamine Esketamine

Note. This table shows a summary of different classifications of atypical antidepressants with example drugs. Only drug classifications approved by the Food and Drug Administration in the United States are included.

The side effects of atypical antidepressants are related to the specific receptors to which they bind.⁵³ Atypical antidepressants can have the same side effects previously discussed with SSRIs.⁵³ When atypical antipsychotics are combined with atypical antidepressants or SSRIs, they can trigger neuroleptic malignant syndrome (Table 1).⁶¹ Atypical antipsychotics antagonize alpha-adrenergic receptors and can cause postural hypotension, or excessive hypotension under general anesthesia.⁵² The chemical structure of bupropion is similar to amphetamine and can cause seizures; therefore, it is contraindicated in patients with seizure disorders.^53,60,62 Mirtazipine is unique because it binds to histamine-1 receptors, which results in sedation, and also suppresses cortisol levels.⁶⁰

Neuroleptic malignant syndrome results from a hypodopaminergic state in the striatum and hypothalamus secondary to dopamine-2 receptor antagonism.⁶³ Typical and atypical antipsychotics are the most common causes of neuroleptic malignant syndrome, but antidepressants and lithium have been known to be contributing factors.⁶³ The differential diagnosis of neuroleptic malignant syndrome and serotonin syndrome may be difficult because they both have overlapping symptoms.⁶³ Additionally, neuroleptic malignant syndrome can be complicated to differentiate from malignant hyperthermia under general anesthesia.⁶⁴ The hallmark symptoms of neuroleptic malignant syndrome include hyperthermia, extreme muscle rigidity, autonomic instability, and altered consciousness.⁶³ The treatment for neuroleptic malignant syndrome includes removing the causative agent and administration of dantrolene in severe cases.⁶³

Ketamine is a phencyclidine derivative that antagonizes the N-methyl-D-aspartate receptor by preventing glutamate binding.⁶⁵ Ketamine is also believed to inhibit MAO reuptake at the presynaptic membrane.⁶⁵ Ketamine has two optical isomers with the S-ketamine being four times more potent than R-ketamine for inducing anesthesia and analgesia.⁶⁵ S-ketamine (intravenous or nasal inhalation) has a rapid onset antidepressant effect that works in one hour and may last up to two weeks, making S-ketamine efficacious in preventing suicides.⁵⁸ The use of ketamine for depression is limited to patients who are suicidal or have failed to respond sufficiently to other antidepressants.⁶⁵

Perioperative Considerations for a Patient on Atypical Antidepressants

The anesthetic implications for atypical antidepressants include all the implications for SSRIs plus additional considerations related to the additional neurotransmitters that are altered.⁵² Atypical antidepressants can be continued in the perioperative period.⁵² The use of low dose ketamine for depression is relatively new, and there is sparse evidence in the literature to generate anesthetic implications.

The major antidepressants that impact dopamine receptor sites include bupropion and all atypical antipsychotics.⁵³ Patients on bupropion must be monitored for seizures.⁶² Patients on both bupropion and atypical antipsychotics are at an increased risk of neuroleptic malignant syndrome.⁶² Neuroleptic malignant syndrome under anesthesia may present similarly to malignant hyperthermia and serotonin syndrome.⁵² Neuroleptic malignant syndrome and malignant hyperthermia are both are treated with dantrolene, hydration, and supportive care.⁵² Muscle rigidity is more pronounced in neuroleptic malignant syndrome, while serotonin syndrome is characterized by myoclonus and hyperreflexia.⁶³ Neuroleptic malignant syndrome is also unique because it can take up to two weeks or more to fully resolve.⁶³ These patients need to be monitored in the intensive care unit for supportive care and observation.⁶³

Lithium

Lithium is the drug of choice as monotherapy to treat bipolar mania and depression.⁵⁰ For unipolar major depression, lithium is used off-label as an effective add-on treatment to other antidepressants.⁶⁶ Lithium is the only drug that has been proven to prevent suicide with long-term treatment.⁶⁶ The exact mechanism of action for lithium is unknown, but it may work by mimicking sodium and reducing the excitability of sodium channels on cell membranes, inhibiting N-methyl-D-aspartate receptors, and increasing serotonin levels.^50,66 Lithium is not metabolized by the body and is dependent on the kidneys for excretion.⁵⁰

Lithium has significant side effects that occur at therapeutic dosages that include cardiac arrhythmias, gastrointestinal disturbances (nausea and diarrhea), tremor, inhibition of antidiuretic hormone, and hypothyroidism.⁵⁰ There is a narrow therapeutic window for lithium with toxicity occurring when plasma lithium levels are higher than 1.5 mEq per liter.⁵⁰ Lithium toxicity is characterized by severe tremors, altered mental status, coma, and nephrotoxicity.⁵⁰ Severe lithium toxicity can result with the co-administration of thiazide diuretics, NSAIDs, meperidine, methylene blue, tramadol, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers.⁵⁰ The administration of angiotensin-converting enzyme inhibitors often results in renal failure.⁵²

Perioperative Implications for a Patient on Lithium

There are several essential anesthetic implications related to patients on lithium. Lithium should be stopped at least twenty-four hours before minor surgeries and up to three days for major surgeries.^50,52 Lithium results in the quicker onset of action and longer duration of all neuromuscular blockers, therefore careful titration of drug dosages using neuromuscular monitoring is suggested.^50,52 Monitor the patients for postoperative residual paralysis. Patients on lithium may have an exaggerated response to sedatives and require a lower minimum alveolar concentration for volatile anesthetics.^50,52 Additionally, adequate hydration perioperatively with normal saline protects against lithium toxicity because increased sodium intake results in increased lithium excretion.⁵² The use of ketorolac (Toradol) is contraindicated because it can raise lithium levels more than 40%, but opioids and acetaminophen are safe.⁵²

Conclusion

Patients with major depressive disorder frequently present for surgery and may be a challenge for anesthesia providers and perioperative nurses due to their illness and the interaction between antidepressants and perioperative medications. All providers involved in the management of patients with major depressive disorder must be knowledgeable about the steps that must be taken to decrease perioperative morbidity and mortality. For patients presenting for elective surgical procedures, preoperative optimization of their depressive symptoms is essential, and the psychiatrist or psychiatric nurse practitioner should be consulted regarding perioperative interruption of antidepressants. If antidepressants are interrupted in the perioperative period, they must be resumed as soon as possible to avoid discontinuation syndrome or rebound of depressive symptoms.

Learning Objectives-.

1. Describe the pathophysiology of major depressive disorder

2. Describe the mechanism of action of antidepressant medications

3. Discuss the perioperative management of patients taking antidepressant medications