Authors: Sung Mee Jung, Sang-Jin Park
Categories: Review article, Anesthesia, Drug interactions, Perioperative period, Psychotropic medication
Source: Journal of Yeungnam Medical Science
Authors: Sung Mee Jung, Sang-Jin Park
Psychotropic medications are widely used in the treatment of mental and nonmental disorders such as chronic pain and other off-label indications. With the increase in comorbidities of mental and physical illnesses, anesthesiologists more frequently encounter patients taking psychotropic medications who require surgical procedures. Commonly prescribed psychiatric medications include antidepressants, mood stabilizers, anxiolytics, and antipsychotics. These medications can interact with anesthetic agents or other drugs commonly used during anesthesia at both pharmacokinetic and pharmacodynamic levels, potentially precipitating life-threatening syndromes such as serotonin syndrome, neuroleptic malignant syndrome, and lithium toxicity. This review summarizes the current knowledge on the pharmacology of commonly prescribed psychiatric medications, including their adverse effects and interactions with anesthetic agents routinely used in the perioperative period. Additionally, considering the risk of withdrawal symptoms and psychiatric relapse or recurrence, current recommendations for the discontinuation or continuation of these medications during the perioperative period are discussed.
The global prevalence of mental health disorders, estimated at approximately 13% in 2019, continues to rise, with major depressive and anxiety disorders experiencing the largest increases in recent years [1,2]. Since many factors influence both mental and physical health, mental disorders influence and are influenced by chronic physical diseases [3-5]. For example, people with mental disorders are at increased risk of a wide range of chronic physical conditions, including diabetes mellitus, cardiovascular disease, stroke, asthma, lung disease, cancer, and substance use disorders. Conversely, patients with chronic diseases are subjected to physical and psychological stress that can trigger the development of depression or anxiety [6]. Owing to the high prevalence of mental illnesses, the prescription of psychotropic medications for the treatment of mental disorders is increasing globally [7-11]. Furthermore, these medications are increasingly used as adjunctive analgesics for pain management and other off-label indications, even in the absence of mental illness. Consequently, anesthesiologists increasingly encounter patients taking psychotropic medications in the perioperative period.
Given their primary effects on neurochemical pathways in the central nervous system (CNS), psychotropic medications can cause serious adverse effects and dangerous interactions with commonly used anesthetic drugs, some of which can be life-threatening [7,8]. Furthermore, because most patients take psychotropic medications long-term [8], it is difficult to determine which medications should be continued and which should not be taken for each patient. The perioperative management of patients taking psychiatric medications has largely relied on clinical experience, with few specific guidelines [9,10]. Therefore, it is crucial for anesthesiologists to have up-to-date knowledge of the pharmacology and potential adverse effects of psychiatric medications, and to provide optimal perioperative management based on the patient’s physical and mental status and severity of the surgery.
The purpose of this article is to review the impact of psychotropic medications on anesthetic management. This review summarizes the pharmacological and adverse effects of commonly prescribed psychiatric medications, including antidepressants, antipsychotics, mood stabilizers, and anxiolytics, as well as their interactions with anesthetics and other medications used in anesthesia. Furthermore, considering the risk of withdrawal symptoms and psychotic relapse, the current recommendations for perioperative discontinuation and continuation of these medications are described.
A review of the current literature from 2000 to 2025 in PubMed was conducted from May to August 2025, with an emphasis on literature published in the past 5 years. The following search terms using keywords and Medical Subject Heading were used for production of this narrative “Psychotropic drugs,” “Psychotropic medications,” “Psychiatric drugs,” “Psychoactive,” “Antidepressants,” “Antipsychotics,” “Mood stabilizers,” “Anxiolytics,” “Benzodiazepines,” “Anxiolytics” AND “Anesthetic implications” or “Anesthetic considerations,” “Anesthetic interactions,” or “Perioperative considerations” (in all combinations). The initial search yielded 548 studies, of which 105 were removed as duplicates. After screening the titles and abstracts, 345 studies were excluded. The authors assessed the full-text articles for eligibility, resulting in 98 included studies (retrospective and prospective studies, systematic reviews, meta-analyses, narrative reviews, clinical guidelines, case reports, and case series). For each selected article, the reference list was reviewed to find additional sources. Considering the heterogeneity of the included studies, a narrative approach to the synthesis was adopted.
Most currently available antidepressants enhance monoamine neurotransmission in the CNS. The most common mechanism is the inhibition of amine reuptake from the synaptic cleft by blocking the membrane transporters for serotonin (SERT), norepinephrine (NET), or both. Amine reuptake inhibitors include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and norepinephrine and dopamine reuptake inhibitors (NDRIs). Another mechanism of action involves monoamine oxidase inhibitors (MAOIs), which inhibit monoamine oxidase metabolism. Additional categories include serotonin receptor antagonist and reuptake inhibitors (SARIs), also known as combined reuptake inhibitors and receptor blockers.
Recently, non-aminergic antidepressants such as N-methyl-ᴅ-aspartate (NMDA) receptor antagonists (e.g., esketamine) and γ-aminobutyric acid (GABA)A receptor modulators (e.g., brexanolone) have emerged as rapid-acting agents (RAAs).
MAOIs inhibit monoamine oxidase metabolism in the outer membrane of mitochondria, thereby increasing the concentrations of norepinephrine (NE), serotonin (5-HT), and dopamine both inside and outside neurons. Monoamine oxidase A (MAO-A) catabolizes 5-HT, NE, and epinephrine, whereas monoamine oxidase B (MAO-B) primarily catabolizes phenylethylamine. Both subtypes catabolize dopamine and tyramine. Classic MAOIs (phenelzine, isocarboxazid, tranylcypromine, and high-dose selegiline) bind irreversibly and non-selectively with MAO-A and -B, and the enzyme requires 1 week to 4 weeks to regain its activity after drug discontinuation. Moclobemide has a more selective and reversible effect on MAO-A, with an elimination half-life of 1 hour to 3 hours. All MAOIs are eliminated via hepatic metabolism.
Possible side effects include dose-dependent hypotension, weight gain, edema, somnolence, insomnia, hypoglycemia, sexual dysfunction, constipation, urinary retention, pyridoxine deficiency, cytochrome P450 (CYP) interactions, and rarely, hepatic toxicity. MAOIs should not be combined with drugs that may cause potentially dangerous interactions in perioperative settings, such as serotonergic agents resulting in serotonin syndrome (SS) and indirectly acting sympathomimetic amines, resulting in hypertensive crisis.
SS is a dose-dependent manifestation of elevated 5-HT levels in neural synapses. MAOIs are the class of antidepressants with the highest risk of SS (Table 1) [11], and their presynaptic release of 5-HT may lead to life-threatening conditions when combined with 5-HT reuptake inhibitors [12,13]. Opioids with weak but sufficient 5-HT reuptake inhibitory activity can be problematic, particularly when administering large doses repeatedly. The potential for drug interactions should be considered in patients taking MAOIs, even when using opioids with a low risk of SS such as fentanyl congeners (e.g., remifentanil, alfentanil, and sufentanil), morphine, hydromorphone, oxymorphone, or buprenorphine [14]. Intermediate-risk opioids (e.g., fentanyl, oxycodone, methadone, and tapentadol) should be used with caution. High-risk opioids (e.g., meperidine and tramadol) should be avoided in patients taking MAOIs.
MAOIs may potentiate drugs that increase blood pressure (BP). Indirectly acting sympathomimetics that increase BP through the release of monoamines (ephedrine and metaraminol) are strongly contraindicated because of their magnified and erratic effects. If necessary, direct-acting adrenergic agonists (e.g., epinephrine, NE, phenylephrine, isoproterenol, and dobutamine) should be started at low doses and titrated appropriately owing to receptor hypersensitivity. High-dose topical cocaine is contraindicated because of serious systemic side effects resulting from its absorption through mucosal surfaces. All local anesthetics, except cocaine, can be safely used for neuraxial anesthesia; however, epinephrine addition may lead to an exaggerated hypertensive reaction in patients taking MAOIs.
As MAOIs are typically used when other antidepressant classes have failed, there are few alternatives for treatment. To prevent psychiatric relapse, it is generally recommended not to discontinue MAOIs without consulting the prescribing psychiatrist (Table 2) [10,15,16]. Additionally, irreversible MAOIs should be discontinued at least 2 weeks before anesthesia and replaced with moclobemide, a reversible MAOI that can be omitted on the day of surgery [9].
TCAs competitively block NE and 5-HT reuptake via neuronal SERT and NET in the synaptic cleft. Secondary amines (nortriptyline and desipramine) predominantly increase NE levels, whereas tertiary amines (amitriptyline and imipramine), which are metabolized to secondary amines, predominantly increase 5-HT levels. The efficacy of TCAs as antidepressants is diminished due to dose-dependent blockade of other receptors (e.g., histamine H1, 5HT2, α1 adrenergic receptors, and muscarinic cholinergic receptors). Currently, TCAs are primarily used for depression that does not respond to commonly used SSRIs or SNRIs. Instead, these drugs are commonly used to treat neuropathic pain, enuresis, and insomnia. TCAs are mostly eliminated by CYP with large inter-individual variation.
Adverse effects include orthostatic hypotension (adrenergic), urinary retention, xerostomia, tachycardia, blurred vision (anticholinergic), and sedation (histaminergic). During the perioperative period, a major concern regarding TCAs is their effect on the cardiac conduction system. TCAs can interact with repolarizing K^+^ channels and Na^+^ channels during depolarization, causing QTc prolongation in an electrocardiogram (ECG) (Table 3) [17,18]. This can lead to dangerous ventricular arrhythmia and sudden cardiac death (SCD). Therefore, patients chronically treated with TCAs should undergo comprehensive cardiac evaluation before anesthesia. During anesthesia, concurrent use of TCAs with drugs that affect the cardiac conduction system, such as halothane, ketamine, and meperidine, should be avoided. Class I antiarrhythmic drugs should be avoided because they potentiate the Na^+^ channel-blocking effects of TCAs.
Similar to MAOIs, TCAs can potentiate the hypertensive effects of indirectly acting sympathomimetics. Direct-acting sympathomimetics should be initiated cautiously at low doses and titrated slowly to prevent hypertensive crisis. Although generally less problematic than MAOIs and SSRIs [11], TCAs still carry a risk of SS. The antimuscarinic properties of TCAs can be potentiated by centrally acting anticholinergics, which may induce anticholinergic toxicity and increase the risk of postoperative delirium, particularly in the elderly population. Orthostatic hypotension due to α1 adrenergic receptor blockade can be significant in patients who are older or dehydrated. All TCAs reduce the seizure threshold, especially when using enflurane [19]. Owing to CYP metabolism, TCAs can potentiate the effects of hypnotics, opioid analgesics, volatile anesthetics, and antibiotics during anesthesia.
Discontinuation of TCAs can lead to withdrawal symptoms, particularly cholinergic symptoms, movement disorders, and cardiac arrhythmias [20]. Delirium, confusion, and depression can also increase postoperatively. Therefore, TCAs should be continued throughout the perioperative period (Table 2) [9,10].
SSRIs primarily block serotonergic reuptake through presynaptic SERT and enhance and prolong serotonergic neurotransmission. SSRIs generally have high affinity for monoamine receptors but lack the affinity for histaminergic, cholinergic (except paroxetine), and α-adrenergic receptors. SSRIs are used to treat major depression, generalized anxiety disorder, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, panic disorder, postmenstrual dysphoric disorder, and bulimia. Currently, SSRIs are the most prescribed antidepressants in clinical practice because of their lower toxicity, superior safety profile, and broader spectrum of use than MAOIs and TCAs. SSRIs include fluvoxamine, citalopram, sertraline, fluoxetine, and paroxetine. Most SSRIs are metabolized by CYP enzymes and some SSRIs or their metabolites inhibit these isoenzymes with at least moderate potency. This may result in increased blood levels of SSRIs and/or other medications or even toxic effects.
Side effects are related to serotonergic potentiation and include gastrointestinal symptoms, xerostomia, headache, anorexia, agitation, drowsiness, sleeplessness, and sexual dysfunction. A major concern regarding SSRIs in the perioperative period is their effect on the risk of abnormal bleeding. SSRIs reduce platelet aggregation by inhibiting serotonin uptake by the platelets [21]. Observational studies have shown an increased risk of gastrointestinal bleeding and intracranial hemorrhage associated with SSRIs [22]. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or direct oral anticoagulants may further exacerbate the risk [22-24]. However, the risk of perioperative bleeding associated with SSRIs has been reported to vary across different types of surgery [25-27].
SSRIs are the drugs most associated with SS (Table 1) [11]. The most dangerous combinations are SSRI plus MAOI or TCA. SSRIs can also cause SS when combined with opioids, such as tramadol and meperidine; anticonvulsants, such as valproic acid; and even antiemetics, such as ondansetron. SSRIs interact significantly with anesthetics by inhibiting the CYP enzymes, particularly the 2D6 isoenzyme. This interaction can increase plasma levels of benzodiazepines, barbiturates, neuromuscular blocking agents, beta-blockers, and antiarrhythmics. High doses of certain SSRIs can lower the threshold for the development of cardiac arrhythmia (Table 3) [28].
Abrupt discontinuation of SSRIs can result in withdrawal symptoms including worsening depression, abdominal pain, nausea, diarrhea, headache, insomnia, dizziness, irritability, and nervousness. Considering the safety and risk of discontinuation syndrome, SSRIs are generally continued throughout the perioperative period (Table 2) [9,10,29]. For patients undergoing surgery with a high risk of bleeding or those taking additional coagulation-altering medications, clinicians should carefully weigh the risk of bleeding against the psychological benefits. For patients with stable depression, gradual tapering of SSRIs over the weeks before surgery, or switching to an antidepressant with less 5-HT reuptake inhibition 2 weeks before surgery, in consultation with a psychiatrist, may be considered [10,30].
SNRIs have a non-tricyclic structure that blocks both SERT and NET, thereby increasing 5-HT and NE neurotransmission. SNRIs are similar to TCAs; however, unlike TCAs, they have minimal affinity for other receptors. Therefore, SNRIs are better tolerated and often preferred over TCAs for the treatment of depression, anxiety, neuropathic pain, and fibromyalgia. Off-label uses include the treatment of stress, urinary incontinence, autism, binge eating disorders, hot flashes, premenstrual dysphoric disorders, and PTSD. Venlafaxine, desvenlafaxine, and duloxetine are more selective for 5-HT, whereas milnacipran and levomilnacipran are more selective for NE.
SNRIs have a side-effect profile similar to that of SSRIs. They may also have noradrenergic effects, including increased BP, heart rate, and CNS activation (e.g., insomnia, anxiety, and agitation). Similar to SSRIs, SNRIs inhibit platelet aggregation. The risk of intraoperative bleeding further increases with the concomitant use of anticoagulants, NSAIDs, or antiplatelet agents (Table 2) [23,24]. Furthermore, a combination of SNRIs and other serotonergic agents can induce SS [11]. SNRIs have relatively fewer CYP interactions than SSRIs. However, duloxetine, a CYP2D6 inhibitor, increases the plasma levels of drugs metabolized via this pathway. In particular, venlafaxine may interact with QTc interval-prolonging drugs, increasing the risk of cardiac arrhythmia (Table 3) [31,32].
All SNRIs have been shown to be associated with withdrawal symptoms similar to those observed when SSRIs are discontinued. Although the risks of bleeding or SS must be considered against the clinical consequences of discontinuation, continuation of SNRI use throughout the perioperative period is generally recommended (Table 2) [10,29]. However, if discontinuation is necessary, a 2-week tapering period is recommended [33].
Atypical antidepressants that engage amine neurotransmission include NDRIs (bupropion); SARIs (trazodone and nefazodone); noradrenergic, specific serotonergic antidepressants (mirtazapine); and those with both 5-HT uptake inhibition and multiple 5-HT receptor agonism and antagonism (vortioxetine). Perioperative concerns regarding atypical antidepressants are similar to those of previously described classes, and the concomitant use of MAOIs is strictly contraindicated for most of these drugs [11].
Esketamine, the S-enantiomer of ketamine, has recently been approved as an RAA for major depressive disorder, particularly treatment-resistant depression. It is also used as an anesthetic and analgesic owing to its NMDA receptor antagonism. When used as an anesthetic, esketamine can induce emergence delirium in preschool children [34]. The most common side effects are dizziness, nausea, dissociation, headache, hypertension, and hallucinations. Furthermore, sedation is enhanced when combined with other CNS depressants [35,36]. No withdrawal symptoms have been observed after the discontinuation of long-term esketamine use [37]. Generally, atypical antidepressants should be continued throughout the perioperative period [10].
Mood stabilizers are used to manage the symptoms of bipolar disorder. The major classes of drugs include lithium, certain anticonvulsants, and second-generation antipsychotics (SGAs).
Lithium is a monovalent cation that mimics Na^+^ in excitable tissues. Lithium passes through voltage-gated Na^+^ channels but is not pumped out by Na^+^-K^+^-ATPase, causing cellular depolarization. The therapeutic mechanism of lithium is likely related to its action on second messenger systems based on phosphatidylinositol turnover.
The narrow therapeutic window (0.8–1.2 mmol/L) of lithium implies that monitoring serum concentration is essential. When the serum concentration exceeds 1.5 mmol/L, adverse effects and toxicity of lithium occur, including vomiting, diarrhea, tremors, and fatigue. When the serum concentration exceeds 2 mmol/L, skeletal muscle weakness, ataxia, sedation, and widening of the QRS complex occur. If the serum concentration reaches 3 to 5 mmol/L, acute lithium toxicity results in various neurological effects ranging from confusion and motor impairment to coma, convulsions, and death. Treatment consists of supportive care, correction of electrolyte abnormalities, and the removal of excess lithium through hemodialysis. Lithium suppresses thyroid hormone release, causing hypothyroidism in approximately 5% of patients. Chronic lithium therapy can cause polyuria because of vasopressin-resistant diabetes insipidus.
Lithium decreases the minimum alveolar concentration (MAC) of volatile anesthetics by blocking the release of NE, epinephrine, and dopamine from the brainstem. Lithium potentiates both depolarizing and nondepolarizing neuromuscular blockade [38]. As lithium is entirely excreted by the kidney, dehydration, acute kidney injury (AKI), and coadministration of NSAIDs, angiotensin-converting enzyme inhibitors, thiazide diuretics, or metronidazole may lead to its accumulation [39]. Preoperative lithium and electrolyte levels, thyroid function tests, and 12-lead ECG should also be assessed. Renal function should be monitored, and drugs that affect renal function should be used cautiously. Neuromuscular blockers should be dose-adjusted using train-of-four monitoring during anesthesia.
Abrupt discontinuation of lithium does not produce physical withdrawal symptoms but carries a risk of manic or depressive relapse. Patients undergoing minor surgery under local anesthesia can safely continue lithium therapy. Because lithium has a long half-life (approximately 24 hours), a patient undergoing major surgery at high risk for significant fluid changes, hemodynamic instability, or AKI should discontinue lithium 72 hours before the surgery and resume the drug once normal electrolyte levels and hemodynamic stability have been attained and the patient is able to eat and drink (Table 2) [9,10].
Anticonvulsants such as valproic acid, carbamazepine, and lamotrigine are commonly prescribed to treat acute manic episodes in patients with bipolar disorder. Anticonvulsants effective in bipolar disorder share the property of sodium channel blockade. SGAs (e.g., aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) have D2 dopamine and 5-HT2A receptor antagonist properties as well as actions on other receptors and amine transporters, contributing to their effectiveness in bipolar disorder. The drug interactions and adverse effects of these agents are lower than those of lithium.
Valproic acid elevates hepatic transaminase levels in ≤40% of patients. It inhibits the metabolism of drugs that are CYP2C9 substrates including phenytoin and phenobarbital. As valproic acid is highly bound to plasma proteins, propofol dosages may be reduced in patients taking valproic acid. It can also cause resistance to nondepolarizing neuromuscular blockers. Another perioperative concern is valproic acid-induced coagulopathy. Although valproic acid decreases platelet counts and reduces the levels of Factor VII, Factor VIII, fibrinogen, and protein C [40-42], its effects on hemostasis remain controversial [41,42].
Carbamazepine is also effective for treating acute manic episodes. It is a potent inducer of CYP and thus accelerates the metabolism of several other drugs, including nondepolarizing amino-steroid neuromuscular blockers. Patients taking carbamazepine may require higher or more frequent doses of neuromuscular blockers. Carbamazepine is also a drug of concern for coagulopathy because it can cause thrombocytopenia, leukopenia, and aplastic anemia [43]. Oxcarbazepine is a weaker, although still clinically significant, inducer of hepatic enzymes than carbamazepine. Lamotrigine, an anticonvulsant, is a mood stabilizer with antidepressant properties and has been approved for the maintenance treatment of bipolar disorder. It is a voltage-sensitive Na^+^ channel blocker and glutamate release inhibitor. As lamotrigine reduces glutamate release, it tends to alleviate dissociative symptoms, particularly in patients receiving ketamine [44,45]. Abrupt discontinuation of anticonvulsant mood stabilizers can lower seizure thresholds. It is generally recommended that they continue throughout the perioperative period (Table 2).
Benzodiazepines enhance the inhibitory effects of GABA. They are effective in treating generalized anxiety disorder, panic disorder, and situational anxiety. Benzodiazepines produce sedative, hypnotic, anesthetic, anticonvulsant, and muscle relaxant effects. Diazepam, lorazepam, and clonazepam are commonly prescribed to treat anxiety, whereas chlordiazepoxide, diazepam, and lorazepam are used to prevent alcohol withdrawal symptoms. Benzodiazepines have the potential for abuse and dependence.
Benzodiazepines cause various side effects, including sedation, mild memory impairment, decreased alertness, and slow reaction times. They synergistically potentiate other CNS depressants, such as opioids, sedatives, and anesthetics. However, in patients with chronic benzodiazepine use, tolerance to the anxiolytic effect increases the MAC of volatile anesthetics. Abrupt discontinuation of benzodiazepines after chronic treatment can lead to serious withdrawal symptoms including increased anxiety, dizziness, and seizures. Therefore, benzodiazepine administration should continue throughout the perioperative period (Table 2). If necessary, gradual discontinuation is crucial.
The effects of antipsychotics are believed to be due to their antidopaminergic effects. Antipsychotics are generally classified into first-generation antipsychotics (FGAs) and SGAs based on their receptor affinity and side-effect profiles. Antipsychotics are used to manage psychosis, particularly schizophrenia, and behavioral symptoms associated with a range of disorders, including bipolar disorder, psychomotor agitation, severe anxiety, agitation, restlessness with dementia, and psychosis associated with Parkinson disease and Huntington disease. Most antipsychotics are metabolized by the hepatic CYP system. Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal side effect that can occur at any time during antipsychotic treatment (Table 4). FGAs carry a higher risk of NMS than SGAs, but SGAs can also cause this side effect.
FGAs, also known as typical or conventional antipsychotics, are presynaptic D2 dopamine receptor antagonists in the CNS. They also block histamine, α1-adrenergic, and cholinergic receptors. FGAs include chlorpromazine, haloperidol, thioridazine, fluphenazine, zuclopenthixol, and many similar compounds.
The main side effects of FGAs are extrapyramidal symptoms (e.g., dystonia, akathisia, and tardive dyskinesia) secondary to dopamine receptor blockade. Chlorpromazine, which causes drowsiness and sedation due to H1 histamine receptor blockade, should be used with caution when used in combination with other CNS depressants. Low-potency dopamine receptor antagonists such as chlorpromazine and thioridazine are commonly associated with anticholinergic side effects (e.g., xerostomia, constipation, and urinary retention) and may produce excess central and peripheral anticholinergic effects in older patients when used with atropine or scopolamine. Chlorpromazine and thioridazine commonly cause orthostatic hypotension by blocking α1-adrenergic receptors and can lower the seizure threshold. Both FGAs and SGAs are associated with ECG changes, including T-wave changes, ST depression, QTc interval prolongation, life-threatening ventricular arrhythmia, and torsade de pointes (TdP), which increase the risk of arrhythmia and SCD (Table 3) [46,47]. Thioridazine induces the greatest QTc prolongation and SCD [48]. Intravenous haloperidol is associated with the highest risk of SCD despite a mean QTc prolongation of 4 to 7 milliseconds. The risk of QTc prolongation and SCD increases with the concomitant use of specific drugs that prolong the QTc interval or in patients with preexisting heart disease [48]. Noncardiac conditions are associated with an increased risk of QTc prolongation, including subarachnoid hemorrhage, cerebrovascular disease, hypothyroidism, hypokalemia, hypomagnesemia, hypocalcemia, obesity, polypharmacy, and age >65 years. Therefore, careful preoperative evaluation of ECG changes and intraoperative cardiac monitoring are necessary in patients taking antipsychotics based on the prescribed agents and additional risk factors for TdP. A QTc >500 milliseconds or a rise in QTc >60 milliseconds above baseline is a clinically significant QTc interval prolongation, which carries a risk of TdP [48].
SGAs, also known as atypical antipsychotics, are D2 dopamine antagonists as well as serotonin (mainly 5-HT2A) receptor antagonists and have fewer side effects, particularly extrapyramidal symptoms, compared to FGAs. SGAs include clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, and brexpiprazole. SGAs are associated with significant weight gain and the development of metabolic syndrome. Clozapine can cause clinically significant agranulocytosis and leukopenia, requiring the monitoring of white blood cell and absolute neutrophil counts. Ziprasidone, olanzapine, and risperidone can cause QTc prolongation and are associated with TdP and SCD, although the risk is much lower than with haloperidol and thioridazine [48-50].
Abrupt discontinuation of antipsychotic medications can lead to rapid-onset psychotic episodes and withdrawal symptoms similar to the cholinergic rebound effects described for TCAs. Therefore, continued use of antipsychotic medication is recommended throughout the perioperative period (Table 2).
If a patient is taking one or more psychotropic medications, the anesthesiologist should be aware of SS or NMS during the perioperative period. Because of their similar clinical presentations, particularly muscle rigidity and hyperthermia, the differential diagnosis of SS and NMS includes malignant hyperthermia (Table 4) [51].
SS, also known as 5-HT toxicity, is a potentially life-threatening drug reaction caused by excessive serotonergic activity in the CNS. It arises from diverse etiologies, including therapeutic drug use, inadvertent drug interactions, and serotonergic drug overdose. SS is characterized by the clinical triad of altered mental status (i.e., delirium, agitation, and confusion), autonomic hyperactivity (e.g., mydriasis, hyperactive bowel sounds, diarrhea, diaphoresis, hypertension, and tachycardia), and neuromuscular abnormalities (e.g., akathisia, tremors, muscle rigidity, hypertonicity, hyperreflexia, and clonus, which are more pronounced in the lower extremities). In life-threatening cases, hyperthermia may arise owing to muscle hypertonicity. Untreated hyperthermia can cause rhabdomyolysis, metabolic acidosis, elevated creatinine levels, renal failure, disseminated intravascular coagulation, and seizures. Sixty percent of SS cases occur within 6 hours of ingesting the causative agent [12].
A striking number of drugs and drug combinations have been associated with SS. SSRIs are the most common cause of SS, followed by opioids, other antidepressants, and SNRIs, while MAOIs carry the highest risk of SS [11]. Pharmacodynamic interactions between drugs with different mechanisms of action can result in more severe SS than a single overdose [12]. The most dangerous combinations are SSRI plus MAOI or SSRI plus TCA.
The perioperative period, a period of rapid succession of opioids and other serotonergic drugs, places patients on serotonergic drugs at an increased risk of SS. During this period, SS presents with broad clinical manifestations, ranging from mild to fatal, and its clinical presentation can mimic other serious conditions, such as malignant hyperthermia, sepsis, thyrotoxicosis, and NMS, making diagnosis challenging. Although there are several diagnostic tools, such as Hunter serotonin toxicity criteria [52], clonus is the most important finding for establishing a diagnosis of SS [12]. Management of SS includes elimination of triggering medications, treatment with cyproheptadine (a 5-HT2A antagonist), and supportive care to manage agitation, autonomic instability, and hyperthermia.
NMS is a rare, but potentially life-threatening condition characterized by severe muscular rigidity (lead pipe), hyperthermia, altered mental status, and autonomic instability (e.g., tachycardia, hypertension, arrhythmia, and diaphoresis) following exposure to dopamine-blocking agents, particularly antipsychotics. Unlike hyperreflexia, clonus, and diarrhea in patients with SS, patients with NMS present with diminished tendon reflex without clonus or gastrointestinal symptoms. Intense rigidity may lead to rhabdomyolysis, myoglobinuria, elevated serum creatinine kinase levels, and renal failure. Symptoms appear 1 to 3 days after drug exposure. SGAs are less common and less severe than FGAs but are associated with all classes of antipsychotics [53-55].
For treatment, antipsychotics should be discontinued immediately, and dantrolene 0.8 to 2.5 mg/kg every 6 hours, up to 10 mg/day is the drug of choice to mitigate hyperthermia and rigidity. Bromocriptine can be used as an alternative treatment. Supportive care, including adequate hydration and cooling, should be provided, with close monitoring of vital signs and serum electrolyte levels.
Psychotropic medications significantly affect perioperative anesthetic management, including drug interactions, toxicity, bleeding risk, potential withdrawal symptoms, and psychiatric relapse. A systematic multidisciplinary approach is essential to ensure patient safety. Anesthesiologists should assess the history of mental disorders and associated psychotropic medication use and then develop an individualized anesthesia plan (i.e., preoperative assessment, careful intraoperative management, and thorough postoperative monitoring) considering the type and extent of surgery and medical comorbidities. When deciding whether to continue or discontinue medication in the perioperative period, the risks of continued use, including drug interactions with anesthetics and common perioperative medications, must be balanced against the risks of discontinuation, including psychiatric relapse or withdrawal symptoms. Most current evidence suggests that psychotropic medications should be continued throughout the perioperative period and discontinued only on an individual basis after careful discussion with the surgeon, anesthesiologist, and psychiatrist, with a clear plan for resumption and monitoring. Given the limited high-quality evidence, further research is needed to develop standardized consensus guidelines for the perioperative management of patients taking psychotropic medications.