Psychiatric manifestations of medications commonly prescribed in otolaryngology.

Abstract

Otolaryngologists, nurses, and psychological professionals should be familiar with the potential psychiatric side effects of medications that are commonly prescribed by otolaryngologists. Because some of these side effects are atypical, their relationship to medications might not be obvious. An awareness of the potential for psychiatric side effects caused by adrenocorticoids, antihistamines and decongestants, and antisecretory medications will help the clinician avoid or detect and treat drug-induced disorders, as will an awareness of the potential for side effects caused by combinations of medications. Identification of individual risk factors such as age, pre-existing organic brain disease, a history of drug abuse or dependence, or coexisting or pre-existing psychiatric disorders is important in preventing and detecting drug-induced psychiatric disorders. The drugs discussed in this article can have serious, even fatal, interactions with certain psychiatric medications.

Introduction

Certain medications routinely prescribed by otolaryngologists can have psychiatric side effects, including mood disturbances (e.g., agitation, anxiety, depression, and mania), perceptual disturbances (e.g., hallucinations and delusions), cognitive disturbances (e.g., delirium and confusion), and behavioral disturbances (e.g., insomnia). Drug-induced psychiatric symptoms can occur even with standard dosages and at any time during the course of treatment.

The combination of some of medications prescribed by otolaryngologists and psychotropic drugs generally prescribed by psychiatrists has the potential to enhance or interfere with the therapeutic effects of one or the other. In addition to psychiatric side effects, other adverse reactions can occur, such as cardiac arrhythmias and hypertension. Certainly, psychiatric symptoms do not always reflect a reaction to a medication, but some can be a manifestation of a coexisting or pre-existing psychiatric disorder that has been aggravated by a combination of medications.

The manifestations of drug-induced psychiatric disorders can be related to direct drug toxicity or to interference with the brain's metabolism of certain drugs. The most common psychiatric symptoms include delirium (an acute reaction with fluctuating awareness of self and environment), confusion, disorientation, tremor, ataxia, and mania. Associated behavioral signs include increased physical activity, rapid speech, insomnia, and mood elevation. Psychiatric symptoms that occur during the course of treatment might also be related to the medical or psychiatric condition being treated. For example, anxiety disorders and panic attacks are known to occur in association with thyroid, parathyroid, and adrenocortical disorders; Langhans' cell endocrinopathies; collagen vascular disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, temporal arteritis, and periarteritis nodosa); and neurotologic disorders (e.g., multiple sclerosis and Meniere's disease). [1] Delusions (the perception that one's environm ent and circumstances seem unfamiliar) can occur in association with certain endocrinopathies. [1] Derealization (the feeling that familiar events seem unreal, strange, or dream-like and that colors, objects, and shapes appear to be distorted) as well as delusions have been reported in systemic lupus erythematosus. [1]

Risk factors for drug-induced psychiatric disorders

As always, a detailed history will help the clinician assess each patient's risk. The history should include the following six questions:

* What prescription medications and over-the-counter medications is the patient currently taking?

* Are there any coexisting medical conditions that can cause psychiatric symptoms?

* Is there a personal or family history of a psychiatric disorder?

* If so, did the disorder manifest at an unusual age or in an atypical form?

* Is there a history of a reaction to a psychiatric drug?

* Is there a history of drug or alcohol abuse?

The patient's age is also an important factor when deciding which medications to prescribe. Elderly patients have a greater risk for drug-induced psychiatric disorders because they tend to be taking more medications and are therefore more likely to experience drug interactions. Older patients also tend to have other medical conditions that can prolong drug metabolism and increase systemic drug levels.

Pre-existing organic brain disease can also be a risk factor for the development of psychiatric side effects, as can drug abuse. Patients who have a history of drug dependence or abuse often manifest delirium. The presence or history of a mood disorder--either depression or mania--is also a risk factor for psychiatric side effects to medications. [2] Adrenocorticoids can aggravate or unmask depression or mania in these patients. Even a family history of mania is a risk factor for the development of mania as a side effect. [2]

Assessment of all risk factors is important because multiple factors in a particular patient can be additive. The overall low incidence of psychiatric side effects with a particular medication might increase in the presence of other factors. An understanding of the risks in every individual patient is essential in selecting medications. Physicians should routinely ask patients to bring in or to make a list of all medications they have taken during the previous 2 months. Clinicians should also inquire as to whether a patient has experienced any side effects or abnormal reactions from any medication previously taken.

Psychiatric side effects of specific drugs

Steroids. Adrenocorticoids are well known to cause psychiatric side effects (table). Delirium, depression, insomnia, mania, and psychoses are not uncommon. These symptoms tend to be proportional in incidence to the dosage and duration of steroid use. Iatrogenic Cushing's syndrome, which can be caused by long-term steroid use, can also manifest and be accompanied by mood changes, depression, euphoria, or mania (table). [2,3]

A personal or family history of affective mental illness can predispose a patient to the psychiatric side effects of steroids. [2] Severe depression might require antidepressant treatment. An antipsychotic medication or mood stabilizer, such as divalproex or lithium, might become necessary to treat steroid-induced mania. Insomnia, either as an isolated side effect or as part of a manic episode, could also require medical intervention.

Antihistamines and decongestants. Antihistamines and decongestants can cause psychiatric side effects either alone or in combination with each other (table). [2,3] These medications can be particularly troublesome because many antihistamines and decongestants can be purchased over the counter (OTC) and are consumed without physician supervision. Moreover, some patients do not even realize that their OTC medications include antihistamine and decongestant components. Also, some patients do not regard OTC medications as "real medicines," and so they do not report them as part of their medical history unless they are specifically asked.

Medications that contain phenylpropanolamine, pseudoephedrine, and phenylephrine are contraindicated in patients who are taking a monoamine oxidase inhibitor (MAOI). [4] These medications can produce dangerously high levels of norepinephrine because the MAOI impairs the metabolism of sympathomimetic medications. [5]

Sympathomimetic medications by themselves can also cause psychiatric side effects. Young children and elderly patients with organic brain syndrome are the most vulnerable. It might become necessary to discontinue the suspected culprit medication or to prescribe sedation with lorazepam or oxazepam or treatment with a high-potency antipsychotic such as haloperidol. Low-potency antipsychotics such as thioridazine or chlorpromazine should not be taken with phenylpropanolamine because the combination can cause hypotension.

The antihistamine and anticholinergic components of a combination antihistamine and decongestant can produce an atropine-like psychosis, typically manifesting as confusion, disorientation, agitation, hallucinations, and memory deficits. Agitation can be treated with a short-acting, nonanticholinergic sedative such as lorazepam or oxazepam. Severe agitation or psychotic symptoms can be treated with low doses of haloperidol. Recovery of the patient's mental status following the administration of physostigmine confirms the diagnosis of atropine-like psychosis. [6] Symptoms should resolve completely after the suspected medication is discontinued.

The hepatic metabolism of many medications is mediated by certain cytochrome P-450 enzymes, and the antidepressants fluvoxamine and nefazodone interfere with certain P-450 enzymes. [7] When these antidepressants are prescribed with other medications that are metabolized by the same P-450 enzymes, competition between the medications for the enzymes impairs the liver's ability to metabolize each as efficiently as usual. This can cause blood levels of these medications to become dangerously high and lead to significant side effects or even a fatal reaction. [7] These antidepressants cannot be used in combination with astemizole for the same reason. Loratadine, fexofenadine, and cetirizine can be used with these antidepressants because they are metabolized by a different cytochrome P-450 isozyme. [7]

Reflux medications. In recent years, otolaryngologists have begun treating more cases of laryngopharyngeal reflux. [8,9] The condition is often detected in patients who have voice complaints. Antisecretory medications, which decrease stomach acid production, are commonly used in the treatment of reflux laryngitis. The two primary classes of drugs prescribed for this condition are the proton pump inhibitors and the [H.sub.2] receptor antagonists. The former includes agents such as omeprazole and lansoprazole, and the latter includes drugs such as famotidine, nizatidine, ranitidine, and cimetidine.

All [H.sub.2] antagonists have been associated with some psychiatric side effects (table). [10] Although the overall incidence of these side effects in outpatients is less than 0.2%, their incidence is significantly higher among hospitalized patients, the elderly, the seriously ill, and those patients who have hepatic or renal failure. [11] The psychiatric side effects of the [H.sub.2] antagonists vary with respect to their time of onset, but they usually resolve within 3 days of discontinuing the drug. For example, ranitidine can cause depression beginning at 4 to 8 weeks after the initiation of treatment. Cimetidine has been reported to cause adverse events within 2 to 3 weeks, and has even caused delirium within 24 to 48 hours. [10] The discontinuation of ranitidine and cimetidine has been associated with a withdrawal syndrome that includes anxiety, insomnia, and irritability. [12] Cimetidine can increase the blood level and action of tricyclic antidepressants, such as amitriptyline, doxepin, imipramine, and nortriptyline; blood levels of these antidepressants can reach toxic levels, resulting in tachycardia and other side effects.

The inhibition of the cytochrome P-450 enzymes by ranitidine or cimetidine can also lead to potentially dangerous side effects with certain other psychiatric medications. (Cimetidine is the more potent inhibitor of the two; ranitidine is one-fifth to one-tenth as potent.) Famotidine and nizatidine do not inhibit this enzyme system at all. [10]

Cimetidine lengthens the half-life of the antianxiety medications clorazepate, chlordiazepoxide and diazepam to a greater degree than does ranitidine. [10] A lower dose of these long-acting benzodiazepines should be considered when they are prescribed for a patient who is already taking cimetidine. An alternative is to use a short-acting benzodiazepine, such as oxazepam or lorazepam. The metabolism of these antianxiety medications is not affected by ranitidine or cimetidine. [10] As another alternative, a different antireflux medication might be selected.

Cimetidine can also increase the blood levels of the serotonin reuptake inhibitors, antipsychotic medications, and anticonvulsants. [13-16] Whenever possible, lower doses of these medications should be given when they are used in combination with cimetidine. The blood levels of these medications should be monitored periodically and their dosages adjusted accordingly. Another option is to use a different [H.sub.2] antagonist such as famotidine or nizatidine.

The combination of the prokinetic medication cisapride and the antidepressants fluvoxamine and nefazodone is of particular concern. [7] These two antidepressants slow the metabolism of cisapride and can cause fatal ventricular arrhythmias. This combination is listed as a contraindication on the drug product information. Another prokinetic medication, metoclopramide, is much safer to use in combination with these antidepressants, although it has been associated with depression and some neurologic side effects. [3,10]

References

(1.) Othmer E, Othmer SC. The Clinical Interview Using DSM-IV. Vol. 1. Washington, D.C.: American Psychiatric Press, 1994:252-9.

(2.) Bernstein JG. Handbook of Drug Therapy in Psychiatry. St. Louis: Mosby, 1995:370-1.

(3.) Bazire S, Benefield WH Jr. Psychotropic Drug Directory: The Mental Health Professionals' Handbook. West Orange, N.J.: Quay Books, 1997:217-36.

(4.) Bernstein JG. Handbook of Drug Therapy in Psychiatry. St. Louis: Mosby, 1995:546.

(5.) Bernstein JG. Handbook of Drug Therapy in Psychiatry. St. Louis: Mosby, 1995:353.

(6.) Bernstein JG. Handbook of Drug Therapy in Psychiatry. St. Louis: Mosby, 1995:384.

(7.) Stahl SM. Psychopharmacology of Antidepressants. London: Dunitz Ltd., 1997:101-8.

(8.) Sataloff RT, Castell DO, Sataloff DM, et al. Reflux and other gastroenterologic conditions that may affect the voice. In: Sataloff RT. Professional Voice. The Science and Art of Clinical Care. 2nd ed. San Diego: Singular Publishing Group, 1997:319-29.

(9.) Sataloff RT, Castell DO, Katz PO, Sataloff DM. Reflux Laryngitis and Related Disorders. San Diego: Singular Publishing Group, 1999.

(10.) Bernstein J. Handbook of Drug Therapy in Psychiatry. St. Louis: Mosby, 1995:380-1.

(11.) Cantu TG, Korek JS. Central nervous system reactions to histamine-2 receptor blockers. Ann Intern Med 1991;l14:1027-34.

(12.) Rampello L, Nicoletti G. [The H2-antagonist therapy withdrawal syndrome: The possible role of hyperprolactinemia]. Medicina (Firenze) 1990; 10:294-6.

(13.) Bernstein JG. Handbook of Drug Therapy in Psychiatry. St. Louis: Mosby, 1995:346.

(14.) Bazire S. Benefield WH Jr. Psychotropic Drug Directory: The Mental Health Professionals' Handbook. West Orange, N.J.: Quay Books, 1997:179.

(15.) Bazire S, Benefield WH Jr. Psychotropic Drug Directory: The Mental Health Professionals' Handbook. West Orange, N.J.: Quay Books, 1997:166.

(16.) Bernstein JG. Handbook of Drug Therapy in Psychiatry. St. Louis: Mosby, 1995:359.

             Selected drugs and their possible psychiatric
                              side effects
Drug                              Side effect
Adrenocorticoids                  Agitation, anxiety, confusion,
                                  delirium,
                                  depression, hallucinations, mania,
                                  paranoia, psychoses, sleep
                                  disturbances
Antihistamines and decongestants
Azatadine                         Agitation, anxiety, euphoria,
                                  hallucinations,
                                  hypomania, mania, nervousness,
                                  somnolence
Loratadine                        Agitation, anxiety, confusion,
                                  delirium,
                                  depression, nervousness
Fexofenadine                      Somnolence
Phenylpropanolamine               Agitation, anxiety, nervousness
[*]/guaifenesin
Pseudoephedrine [+]/guaifenesin   Hallucinations
Antisecretory agents
Cimetidine                        Confusion, delirium, depression,
                                  hallucinations, mania, paranoia
Famotidine                        Agitation, anxiety, depression,
                                  nervousness
Lansoprazole                      Hallucinations
Nizatidine                        Agitation, anxiety, nervousness,
                                  somnolence
Omeprazole                        Aggression, agitation, anxiety,
                                  depression,
                                  hallucinations, hostility,
                                  nervousness,
                                  violence
Ranitidine                        Confusion, delirium, depression,
                                  hallucinations, mania

(*.)Agents containing phenylpropanolamine can also cause confusion, delirium, depression, euphoria, hallucinations, hypomania, mania, and paranoia.

(+.)Agents containing pseudoephedrine can also cause agitation, anxiety, euphoria, hypomania, mania, nervousness, and paranoia.