Diarrhea, Hypermotility, and Constipation
Loose stools may occur during initiation of treatment with serotonergic antidepressants or as part of discontinuation syndromes upon abrupt cessation of these drugs. Loose stools are usually self-limited phenomena that can be managed conservatively (e.g., via oral replenishment of fluid losses and over-the-counter remedies such as loperamide or bismuth subsalicylate).
Serotonergic antidepressants may cause gastrointestinal (GI) hypermotility, usually near treatment initiation. Symptoms are usually self-limited and resolve with time on the drug. As identified in manufacturers’ product information materials, FDA registration trials of SSRIs across their indications collectively report incidence rates of diarrhea that are generally within the range of ~6%–20%, with the highest being vilazodone (28%). Some SNRIs (e.g., duloxetine, desvenlafaxine) identify lower rates (~10%), while the lowest rates among antidepressants (>1%–2%, but no different from placebo) are described with bupropion XL, mirtazapine, and venlafaxine XL. Among mood-stabilizing agents, significant or persistent diarrhea with lithium or divalproex should be considered as a possible indicator of drug toxicity. Frank microscopic colitis also has been associated with paroxetine, sertraline, and carbamazepine, remediable by drug cessation (Beaugerie and Pardi 2005).
When necessary, conservative interventions to manage diarrhea symptoms include increasing dietary fiber (e.g., psyllium husk–containing products, such as Metamucil), use of aluminum hydroxide (e.g., Amphojel) products, cyproheptadine, or over-the-counter antidiarrheal medicines such as loperamide or bismuth subsalicylate. Oral probiotics (e.g., lactobacillus acidophilus) also represent popular nonprescription antidiarrheal remedies, but their potential efficacy for psychotropically induced GI hypermotility has not been formally studied. Severe or persistent diarrhea in the absence of other identified etiologies may warrant drug cessation.
Constipation is among the more common adverse effects associated with drugs that possess antimuscarinic anticholinergic properties (e.g., many SGAs, TCAs, benztropine, and some SSRIs [notably, paroxetine]). Anticholinergic antipsychotics (e.g., clozapine) may cause constipation in up to half of patients. Assessment should rule out the possibility of a functional bowel obstruction (e.g., failure to pass gas, distended abdomen with crampy abdominal pain, nausea/vomiting). Clozapine-induced gastrointestinal hypomotility is a rare and potentially lethal adverse effect associated with high doses or concomitant anticholinergic drugs that can cause bowel obstruction, megacolon, necrosis, and intraabdominal sepsis.
Similar incidence rates for constipation (ranging from ~3% to 16%) have been reported in manufacturers’ product information materials from FDA registration trials involving SSRIs, SNRIs, bupropion, and mirtazapine. Clinicians obviously should, when possible, attempt to minimize the cumulative anticholinergic burden of an overall drug regimen. Short-term use of bulk-forming hydrophilic laxatives (e.g., methylcellulose, psyllium seed), stimulant laxatives (e.g., senna), or cathartic osmotic laxatives (e.g., lactulose) offer relatively conservative first-line interventions, while agents that stimulate peristalsis (e.g., metoclopramide or bethanechol) may offer additional mechanistically specific strategies to counteract anticholinergic-associated constipation.
SSRIs, particularly in combination with NSAIDs or aspirin, may increase the risk for upper GI bleeding. In SSRI recipients with a history of peptic ulcer disease or upper GI bleeding, gastroprotective cotherapy (e.g., with a proton pump inhibitor) may be advisable.
SSRIs have been associated with an approximate 2-fold increased risk for upper GI bleeding, with a crude incidence rate of 1 in 8,000 SSRI prescriptions (Andrade et al. 2010). Mechanisms thought to account for this phenomenon include decreased platelet aggregation due to inhibition of serotonin uptake from blood into platelets, as well as a direct effect causing increased gastric acid secretion (see further discussion in Chapter 14, “Hematological System,” in the section on platelet aggregation disorders and bleeding risk). SSRIs (but not TCAs) have also been shown to increase the risk for peptic ulcer disease by 1.5-fold, with a 24% reduction in risk observed with concomitant proton pump inhibitors (e.g., omeprazole, lansoprazole, or pantoprazole) (Dall et al. 2010). Identified risk factors for upper GI bleeding during SSRI therapy include concomitant use of NSAIDS, aspirin, or antiplatelet drugs (conferring an 8- to 28-fold increased likelihood) or the presence of liver failure or cirrhosis (Andrade et al. 2010), while cotherapy with proton pump inhibitors among SSRI recipients as a group may reduce bleeding risk (Dall et al. 2009). No increased risk of lower GI bleeding during SSRI treatment has been reported.
Some authors advocate the coadministration of a proton pump inhibitor or other gastroprotective agent (e.g., H2 histamine blocker) in SSRI recipients with a history of upper GI bleeding or peptic ulcer disease, although the low absolute risk for upper GI bleeding likely obviates the necessity of gastroprotective measures for most SSRI recipients. Some authors also advise the discontinuation of SSRIs before elective surgery in patients with a history of upper GI bleeding, although such decisions are usually made on a case-by-case basis depending on the nature of the surgery and the presence of other risk factors for increased bleeding.
Hepatic Impairment and Transaminitis
Most psychotropic drugs require lower dosing in the setting of hepatic failure, but few absolute contraindications exist for use of these drugs in patients with hepatic dysfunction. Although many anticonvulsants and some antidepressants and SGAs can infrequently raise hepatic enzyme levels, routine laboratory monitoring is generally less useful or relevant than regular clinical monitoring for signs and symptoms suggestive of hepatotoxicity.
The evaluation of hepatic function involves assessment of liver enzymes (i.e., ALT and AST), as well as other enzymes (e.g., alkaline phosphatase) and synthetic proteins made by the liver (e.g., serum albumin, total protein, total bilirubin, prothrombin time). AST:ALT ratios of 2:1 or 3:1 often suggest alcohol-induced hepatotoxicity. The detection of recent heavy alcohol use can be aided by the measurement of serum carbohydrate-deficient transferrin, a highly specific but only moderately sensitive marker for drinking behavior. γ-Glutamyl transpeptidase (γGTP), another enzyme synthesized exclusively by the liver, is a nonspecific measure of liver dysfunction that is sometimes used as an indicator of even modest alcohol consumption or as a means to clarify hepatic- versus bone-based causes of an elevated serum alkaline phosphatase. An elevated γGTP level also may occur in congestive heart failure or other conditions that involve liver injury and by itself does not help to distinguish a cause for hepatic dysfunction.
Medication-induced hepatotoxicity often involves serum ALT > AST. In overweight individuals at risk for metabolic syndrome, mild transaminitis (in which ALT and AST levels usually do not exceed 4 times the upper limit of normal) may reflect nonalcoholic steatohepatitis, a hepatic inflammatory condition affecting 2%–5% of Americans (particularly middle-aged, overweight adults) that can lead to hepatocellular damage, fibrosis, and eventual cirrhosis. Importantly, 10%–25% of Americans have simple fatty liver without inflammation (nonalcoholic fatty liver disease), addressable by treating the underlying metabolic risk factors (particularly obesity and hyperlipidemia).
Many psychotropic drugs, including divalproex, carbamazepine, TCAs, SNRIs, and SGAs, can be associated with modest elevation of serum liver enzyme levels. For example, incidence rates of transaminitis with carbamazepine in epilepsy patients range from 5% to 15%, although fewer than 20 cases of significant liver impairment were reported over a 12-year period studied (Pellock and Willmore 1991). Frank hepatotoxicity has been reported in connection with the use of carbamazepine, divalproex (■), duloxetine, and nefazodone (■). Hepatic enzyme elevation may be caused by numerous nonpsychotropic medications, including acetaminophen, NSAIDs, statins, ACE inhibitors, omeprazole, allopurinol, certain antibiotics, and oral contraceptives, among others. There are no formal manufacturers’ recommendations or guidelines on the indications for monitoring of liver enzymes, with the exceptions of divalproex and carbamazepine (see Table 1–2 in Chapter 1, “The Psychiatrist as Physician”), unless indicated based on the emergence of clinical signs (e.g., icteric sclerae or jaundice, changes in stool color).
Some authorities point out that regular, routine laboratory monitoring of liver enzymes or other parameters that reflect hepatic function (e.g., prothrombin time, partial thromboplastin time, protein levels) are often normal in anticonvulsant recipients who subsequently develop hepatotoxicity; more relevant to safety monitoring is the ability to recognize clinical signs of hepatic failure (e.g., nausea, vomiting, anorexia, lethargy, jaundice) (Pellock and Willmore 1991).
In general, most hepatically cleared drugs can be continued unless liver enzymes exceed 3 times the upper limit of normal. That generalization reflects one of three pillars that has come to be known as Hy’s law (Reuben 2004), a principle relevant for gauging the likelihood of fatal drug-induced liver injury. Other components of this triad include total serum bilirubin >2 times the upper limit of normal, and absence of another etiology (e.g., alcoholic hepatitis, hepatic ischemia).
Preexisting liver disease (e.g., hepatitis, alcoholic liver disease) does not automatically contraindicate use of hepatically metabolized psychotropic drugs. Degrees of hepatic impairment are rated with the Child-Pugh classification scale (see Table 3–1 in Chapter 3, “Vulnerable Populations”), which takes into account total bilirubin, serum albumin, ascites, INR, and presence of hepatic encephalopathy. The extent to which hepatic dysfunction may alter drug clearance, and potentially necessitate hepatic dosing of psychotropic medications, is summarized in Table 12–1.
In patients with an acute mental status change who are taking divalproex or carbamazepine, serum ammonia level should be measured to determine the possible presence of hyperammonemia. If either of these agents is the suspected cause of hyperammonemia, discontinue the drug and consider administration of L-carnitine 1,000 mg twice daily and/or lactulose to hasten the elimination of serum ammonia. Asymptomatic hyperammonemia caused by divalproex or carbamazepine does not necessarily require intervention.
Laboratories vary in defining reference range upper limits for serum ammonia levels, although levels exceeding 70 μg/dL in adults are generally thought to reflect clinically significant elevation. Hyperammonemia may be associated with hepatic encephalopathy and warrants consideration in the differential diagnosis of patients with an acute mental status change when hepatic disease (e.g., cirrhosis, hepatitis, alcohol withdrawal) may be present. Clinicians should be attentive to the presence of vomiting and asterixis or other focal neurological signs (e.g., hyperreflexia) when considering the possibility of hepatic encephalopathy.
Anticonvulsants and lithium
Caution is advised when used in patients with hepatic dysfunction.
Drug is contraindicated in the setting of significant hepatic dysfunction.
Drug is not appreciably metabolized and is excreted unchanged; dosing adjustment in the setting of hepatic disease therefore is unnecessary.
Dosing should be reduced by 25%–50% in the setting of moderate or severe hepatic impairment, according to the manufacturer’s package insert. Metabolized by Phase II glucuronidation.
All preparations of lithium are renally excreted with no hepatic metabolism; no dosing adjustment is necessary in the setting of hepatic failure.
No dosing adjustment is necessary in patients with mild to moderate hepatic impairment; caution is advised when used in patients with severe hepatic dysfunction.
Dosing should be reduced and intervals between doses should be increased in the setting of hepatic dysfunction.
Antidepressants and related agents
Initial dosing should be reduced by 50% in patients with moderate hepatic impairment and by 75% in those with severe hepatic impairment.
Caution is advised in the setting of mild to moderate hepatic impairment; in severe hepatic impairment, the manufacturer of bupropion XL advises dosages no higher than 150 mg every other day.
Hepatic insufficiency may increase serum buspirone levels 13-fold. The manufacturer advises against using buspirone in individuals with severe hepatic dysfunction.
Oral clearance of mirtazapine is decreased by approximately 30% with hepatic insufficiency. Consequently, dosages should be reduced in patients with moderate or severe hepatic impairment.
Plasma concentrations increase by ~25% in the setting of liver disease. Boxed warning (■) indicates that nefazodone should not be administered in patients with active liver disease or when liver enzymes exceed 3 times the upper limit of normal.
Desvenlafaxine: In mild to moderate impairment, dosing should be reduced by at least 50%. Desvenlafaxine should not be dosed >100 mg/day in the setting of hepatic impairment.
Duloxetine: Administration is not recommended for patients with any hepatic insufficiency.
Levomilnacipran: No dosing adjustment is necessary per the manufacturer in the setting of mild, moderate, or severe hepatic impairment.
Venlafaxine: In mild to moderate impairment, dosing should be reduced by at least 50%.
Citalopram: Half-life approximately doubles in the setting of hepatic dysfunction; a dosage of 20 mg/day is recommended.
Escitalopram: A dosage of 10 mg/day is recommended with hepatic impairment.
Fluoxetine: Lower or less frequent doses are advised.
Fluvoxamine: Plasma clearance is decreased by ~30%; low initial dosing is advised.
Paroxetine: Plasma concentrations are increased approximately 2-fold; low initial dosing is advised.
Sertraline: Plasma concentrations are increased approximately 3-fold; low initial dosing is advised.
No dosing adjustment is necessary in patients with mild or moderate hepatic impairment.
No dosing adjustment is necessary in patients with mild or moderate hepatic impairment.
The manufacturer recommends no need for dosing adjustments in the setting of mild, moderate, or severe hepatic impairment.
The manufacturer advises no need for dosing adjustment in the setting of mild to moderate hepatic impairment and a maximum dose of 2 mg/day in the setting of severe hepatic impairment.
The manufacturer notes that drug exposure increases 4-fold in the setting of mild hepatic impairment and >10-fold in patients with severe hepatic failure (for whom caution is advised if using ramelteon).
No dosing adjustment needed in mild or moderate hepatic impairment; the manufacturer advises against using suvorexant in patients with severe hepatic impairment.
The manufacturer advises no necessary dosing adjustments in the setting of mild to moderate hepatic impairment (Child-Pugh scores ≤ 9) but recommends against using tasimelteon in patients with severe hepatic impairment (Child-Pugh scores of 10–15).
The manufacturer recommends maximum dosing of 5 mg/day in patients with mild to moderate hepatic impairment and discourages use of zolpidem in the setting of severe hepatic impairment.
No dosing adjustment is necessary in the setting of any hepatic impairment (Child-Pugh scores of 5–15).
Drug is not recommended for use in patients with hepatic failure. It is metabolized by Phase I oxidation (CYP1A2) and Phase II glucuronidation (UGT1A4).
In moderate to severe hepatic impairment (Child-Pugh scores ≥ 7), the manufacturer’s maximum recommended dose is 2 mg/day (major depressive disorder) or 3 mg/day (schizophrenia).
The manufacturer advises no necessary dosing adjustments in patients with mild to moderate hepatic impairment (Child-Pugh scores of 5–9) but avoidance of cariprazine in the setting of severe hepatic impairment (Child-Pugh scores of 10–15).
In moderate or severe hepatic impairment, maximum dosage recommended by the manufacturer is 40 mg/day.
Mild hepatic impairment (Child-Pugh scores of 5–9) produces little effect on clearance of olanzapine.
No dosing adjustments are necessary for mild to moderate hepatic impairment.
The manufacturer advises that patients with hepatic impairment begin treatment at 25 mg/day, with daily increases of 25–50 mg/day based on clinical response and tolerability.
In the setting of hepatic impairment, dosage increases should be no higher than 0.5 mg twice daily, and increases above 1.5 mg twice daily should occur at least 1 week apart.
No dosing adjustments are necessary for mild to moderate hepatic impairment.
Note. CYP=cytochrome P450; SGA=second-generation antipsychotic; SNRI = selective norepinephrine-serotonin reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; XL=extended release.
In the early 1980s, case reports began to emerge describing asymptomatic hyperammonemia as well as hyperammonemic encephalopathy in both child and adult epilepsy patients taking divalproex. A prospective case series by Raja and Azzoni (2002) identified asymptomatic hyperammonemia (serum ammonia>97 μg/dL) with normal liver enzyme levels in 51% of adult psychiatric inpatient recipients of divalproex, ameliorated solely by divalproex dosage reductions. Divalproex-associated hyperammonemia may be clinically asymptomatic in about half of cases. Notably, no clear correlation has been demonstrated between asymptomatic hyperammonemia (or even valproate-related hyperammonemic encephalopathy) and serum valproate levels. The clinical significance of asymptomatic hyperammonemia due to divalproex is uncertain, although serum ammonia levels >127 μg/dL may be more likely associated with encephalopathy irrespective of serum valproate levels.
Hyperammonemia has also been reported as an idiosyncratic phenomenon in association with carbamazepine in the absence of laboratory indices of hepatic impairment, remedied by oral lactulose and the cessation of carbamazepine. Other possible causes of hyperammonemia include barbiturates, opiates, diuretics, and cigarette smoking, as well as hemolytic processes (e.g., GI bleeding), reduced ammonia clearance due to fulminant hepatic failure (e.g., following acetaminophen overdose), and inborn errors of metabolism in both children and adults. Excessive exercise or seizures can also increase direct ammonia production from skeletal muscle.
Numerous factors can predispose to the development of hyperammonemia among divalproex recipients, including severe alcoholism, high dietary nitrogen intake in the setting of low caloric intake, urea cycle disorders among pediatric patients, and combinations of anticonvulsant drugs among epilepsy patients. Hyperammonemia is thought to result from the effects of propionic acid (a metabolite of divalproex that inhibits carbamoyl phosphate synthetase, in turn impairing the conversion of ammonia to urea in the urea cycle). Additionally, divalproex may directly elevate serum ammonia levels by depleting body stores of carnitine, a quaternary ammonium compound synthesized from the essential amino acids methionine and lysine in the liver that is a necessary cofactor for β-oxidation of fatty acids. Measurement of serum carnitine levels is thought to be uninformative in estimating its bioavailability in the liver because it is stored mainly in muscle. The use of oral lactulose is generally reserved for hyperammonemic patients who manifest clinical signs of encephalopathy.
Case reports have suggested that supplemental dietary L-carnitine (1 g po bid) can reverse signs of lethargy and mental slowing in the setting of otherwise asymptomatic hyperammonemia during divalproex therapy. There is presently no consensus recommendation within the field as to the necessity for routinely monitoring serum ammonia levels in the absence of lethargy or other CNS features suggestive of encephalopathy, or in routine supplementation of oral L-carnitine in asymptomatic divalproex recipients. In our experience, given the relative rarity of symptomatic hyperammonemia and the dubious clinical significance of its asymptomatic presence, we concur with the manufacturer in not advocating routine measurement of serum ammonia levels during divalproex treatment, although it likely warrants evaluation in patients taking divalproex who develop acute mental status changes, for which treatment with supplemental L-carnitine (1 g bid) may be ameliorative.
Some anticonvulsants may interfere with absorption or metabolism of vitamin B12 and folic acid. Folic acid supplementation is commonly recommended during anticonvulsant therapy in pregnancy to minimize risk for neural tube defects. However, routine screening or repletion of these vitamins during anticonvulsant therapy in nonepileptic patients generally is not done in the absence of clinical signs of deficiency.
Low serum levels of vitamin B12 (cobalamin) and folic acid found in epileptic adults have been associated with a number of anticonvulsants, including carbamazepine, divalproex, gabapentin, oxcarbazepine, and topiramate (but not lamotrigine or zonisamide) (Kishi et al. 1997; Sander and Patsalos 1992). Impaired GI absorption has been proposed as one possible mechanism, although other plausible explanations for this phenomenon include impaired plasma binding, disrupted renal secretion, and (at least in the case of carbamazepine, oxcarbazepine, or topiramate) hastened metabolism via induction of CYP microenzymes (Linnebank et al. 2011). Because folic acid and vitamin B12 are necessary to convert homocysteine to methionine, deficient levels can elevate plasma homocysteine, in turn predisposing to vascular endothelial damage and cardiovascular or cerebrovascular disease. Clinically, low levels of vitamin B12 or folic acid may also cause megaloblastic anemia, neuropathy, cognitive deficits, and osteoporosis, among other metabolic or homeostatic disturbances. Low serum folic acid levels due to anticonvulsant exposure during pregnancy are well-recognized contributors to neural tube defects (see the section “Breast-Feeding and Teratogenicity” in Chapter 21, “Pregnancy and the Puerperium”). Although some authors advocate periodic laboratory monitoring of serum folic acid and vitamin B12 levels during therapy with most anticonvulsants in women (irrespective of pregnancy status) as well as men, with repletion (e.g., 1 mg/day of oral folic acid [Morrell 2002] or 1,000–2,000 μg/day of oral vitamin B12 [Kuzminski et al. 1998]), there is no formal recommendation by the American Epilepsy Society or the American Academy of Neurology either for routine serum monitoring or replacement therapy in asymptomatic anticonvulsant recipients.
Nausea and Gastrointestinal Upset
Nausea often occurs as a transient side effect from serotonergic antidepressants that indiscriminately stimulate postsynaptic serotonin type 3 (5-HT3) receptors, and may be minimized by coadministration with food or over-the-counter antiemetics such as bismuth subsalicylate or antihistamines. Prescription-strength antihistamine antiemetics, such as trimethobenzamide or promethazine, may be useful if significant nausea persists.
Serotonergic agents commonly cause nausea due to their undesirable affinity for 5-HT3 receptors, resulting in the most frequent adverse effect associated with SSRIs. Accordingly, psychotropic agents that block postsynaptic 5-HT3 receptors (notably, mirtazapine or olanzapine) have a lower likelihood for causing nausea than do drugs that nonselectively agonize this receptor and may in fact possess potent antiemetic properties. The novel serotonergic antidepressant vortioxetine was associated with an approximate 20%–30% incidence of dose-dependent, mild to moderate nausea, mainly in the first 2 weeks of exposure, during FDA registration trials; however, since this drug is a potent 5-HT3 antagonist (Ki=~3.7 nM), the mechanism by which it may produce nausea is likely related to other receptors or transmitter systems (e.g., 5-HT1A agonism). Consequently, anti-nausea drugs that exert their effects via 5-HT3 antagonism (e.g., ondansetron, granisetron) would represent less compelling treatment options to remedy vortioxetine-associated nausea because vortioxetine already blocks 5-HT3 receptors. Ondansetron has formally been studied to treat or prevent nausea and vomiting from emetogenic cancer chemotherapy, radiation therapy, or postoperative nausea and vomiting, although it is commonly used “off label” in emergency departments and other medical settings to treat nausea and vomiting from other etiologies, with comparable efficacy to prochlorperazine. Anti-nausea pharmacotherapies that are unrelated to 5-HT3 binding might include trimethobenzamide, prochlorperazine, or metaclopramide.
Nausea and GI upset are usually transient phenomena with most psychotropic medications that cause them. Antipsychotic drugs generally do not cause nausea, and some in fact are commercially marketed as antiemetics (e.g., phenothiazines such as prochlorperazine, or the dopamine D2 antagonist metoclopramide)—albeit with high risk for extrapyramidal side effects by virtue of their D2 antagonistic effects, including in the chemoreceptor trigger zone. Patients’ complaints of nausea should be evaluated not only from the standpoint of their acclimation to a new drug but also as possibly indicating erratic treatment adherence with frequent missed doses and withdrawal states. Anecdotally, compared with branded formulations, generic formulations of serotonergic antidepressants may be more likely to cause nausea and GI upset. Specifically, in the case of lithium, long-acting preparations that are absorbed more distally in the GI tract (e.g., Eskalith CR) or lithium citrate solution may be associated with less upper GI upset but potentially more lower GI symptoms (e.g., loose stools or diarrhea).
Adjunctive pharmacotherapies may sometimes be appropriate and useful to counteract transient nausea, although a more overriding concern is determining whether nausea represents a more serious adverse drug effect (e.g., pancreatitis from divalproex) or drug toxicity state (e.g., elevated lithium levels). In patients taking lithium, associated neurological signs (e.g., ataxia, tremor) or other GI symptoms (e.g., abdominal cramping) should alert the clinician to recognize nausea as a potential indicator of drug toxicity rather than merely a benign adverse effect remediable by symptomatic treatment. Antihistamines with antiemetic properties, such as trimethobenzamide (300 mg tid prn) or promethazine (12.5–25 mg bid prn), are perhaps the most reliable and safe pharmacological interventions for transient nausea. Antiemetic phenothiazines such as prochlorperazine or the D2 antagonist/5-HT3 antagonist metoclopramide also may be of value, although their potential for causing movement disorders due to their nigrostriatal antidopamine effects limits enthusiasm for their long-term use. (The FDA has approved use of metoclopramide for no longer than 4–12 weeks.)
Patients who develop an acute abdomen require prompt evaluation. Patients taking divalproex, or less commonly, some SGAs (e.g., quetiapine, olanzapine, clozapine), should be assessed for iatrogenic pancreatitis through physical examination, measurement of serum lipase and amylase, and possible radiographic evaluation. In the setting of acute pancreatitis, the aforementioned drugs should be discontinued and not reintroduced.
Divalproex (both delayed- and extended-release formulations) may rarely be associated with the development of acute pancreatitis (■). The mechanism by which this may occur is not well understood. From 1979 to 2005, 90 cases were reported worldwide, although the true incidence may be underrecognized and underreported (Gerstner et al. 2007). Cases have been reported to occur during both recent and long-term treatment, up to 19 years after drug initiation (Taira et al. 2001). Routine screening of serum lipase or amylase levels in divalproex recipients is neither recommended nor clinically indicated in the absence of clinical signs that are suggestive of acute pancreatitis (i.e., development of an acute abdomen). Pancreatitis does not appear to be a class adverse effect among anticonvulsants, although rare case reports have been published that involved lamotrogine as part of DRESS syndrome (see section “Antiepileptic Hypersensitivity Reactions” in Chapter 20, “Systemic Reactions”), as well as carbamazepine, and levetiracetam. Gabapentin and pregabalin have also been described as viable treatments for pancreatitis-associated visceral pain.
Some SGAs (e.g., quetiapine, olanzapine, clozapine) have been associated with acute pancreatitis independent of hypertriglyceridemia or hyperglycemia, arising via poorly understood mechanisms. Rare case reports also exist of recurrent pancreatitis arising in connection with the use of mirtazapine.
Many nonpsychotropic drugs can also cause acute pancreatitis; these include estrogen, calcium, anticholinesterases, thiazide diuretics, pentamidine, ACE inhibitors, furosemide, tetracycline, metronidazole, isoniazid, rifampin, sulfonamides, cyclosporine, asparaginase, vinca alkaloids, and other antineoplastic drugs. Careful attention should be paid to other factors that may predispose patients to acute pancreatitis—notably, alcohol abuse or dependence (which often may be comorbid with conditions for which divalproex or an SGA may be used, such as bipolar disorder or impulsive aggression)—or hyperlipidemic states. Divalproex or the aforementioned SGAs should be discontinued and not reintroduced following identification and proper medical management of acute pancreatitis.
The symbol ■ is used in this chapter to indicate that the FDA has issued a boxed warning for a prescription medication that may cause serious adverse effects.