Antidepressant use in psychiatry and medicine

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Antidepressant use in psychiatry and medicine Importance for dental practice JOSEPH J. KEENE JR., D.D.S., M.S.; GAIL T. GALASKO, B.Sc.(HONS), M.Sc., Ph.D., M.R.S.C.; MARTIN F. LAND, D.D.S., M.S.D.

ntidepressants are prescribed for diverse therapeutic reasons, including a variety of psychiatric disorders,1-5 pain control,6-20 insomnia,21,22 smoking cessation,23 substance abuse24,25 and eating disorders.26 27 Xerostomia, orthostatic hypotension 28 and cardiotoxicity29 are significant adverse effects related to the use of certain classes of antidepressant mediPatients cations, especially when they are taken with other medicareceiving in conjunction tions.30,31 Patients receiving antidepresantidepressant sant therapy commonly complain of therapy are at decreased salivation and changes in risk of salivary viscosity.32 Chronic xerostomia can contribute to oral mucosal changes, developing increased coronal and root caries susxerostomia and ceptibility, candidiasis, partial loss of orthostatic taste acuity, periodontal disease, diffihypotension. culty in swallowing and functional prosthetic problems.33-36 Antidepressants are prescribed for patients of all ages.37,38 von Knorring and Wahlin37 reported a higher incidence of caries in children receiving antidepressant therapy. In patients aged 60 years or older, Thomson and colleagues39 reported a higher root caries index value for those receiving antidepressant therapy compared with control subjects. They noted a potential additive xerostomic effect when antidepressants were taken concurrently with other xerostomia-producing medications. Budtz-Jorgensen and colleagues40 reported that xerostomia has a potentially negative effect on masticatory function and nutritional intake in elderly people. Cardiovascular complications are associated with the

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ABSTRACT Background. Many dental patients receive antidepressant therapy. However, antidepressants taken with other drugs may increase the risk of complications that require special dental precautions and care. Methods. The authors conducted a retrospective study of 1,800 randomly selected patient records and evaluated the prevalence of using antidepressants and other medications concurrently. They analyzed antidepressant intake relative to drug classification and mechanism of action, age, sex and associated potential for clinical complications such as xerostomia, orthostatic hypotension and interaction with vasoconstrictors. The potential for additive adverse effects between antidepressants and other medications also was analyzed. Results. Three hundred eighty-one (21 percent) of the 1,800 patient records indicated that patients were being treated with 412 antidepressants. Female subjects outnumbered male subjects by an approximate 2.3:1 ratio. Selective serotonin reuptake inhibitors were most commonly prescribed, followed by tricyclic antidepressants, atypical and third-generation antidepressants, and monoamine oxidase inhibitors. Based on reported medication intake, almost 58 percent of subjects in the antidepressant group were receiving treatment with two or more medications that had the potential for producing xerostomia. Two hundred fiftyseven (67 percent) of the 381 records documented intake of an antidepressant or other medication with orthostatic hypotension potential. Conclusions. Three hundred eighty-one patients reported that they were receiving antidepressant therapy for psychiatric and other medical reasons. Potential adverse effects and interactions with other medications have direct implications for dental treatment. Clinical Implications. Patients receiving antidepressant therapy are at risk of developing xerostomia and orthostatic hypotension, as well as experiencing the adverse effects of interaction with vasoconstrictors. Dentists must take appropriate precautions in treating these patients.

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use of specific antidepressants. Medicationinduced orthostatic hypotension increases in the elderly and in medically compromised patients, and several authors41-43 have reported a 10 to 30 percent increased risk of syncope, falls and injury. Of clinical importance is that serious pressor responses can result from certain antidepressants when local anesthetics containing vasoconstrictors are administered, particularly when the patient has pre-existing cardiovascular disease.44-46 The dental concerns associated with adverse effects of antidepressant therapy led to this retrospective study. We randomly selected and reviewed a total of 1,800 dental records. The prevalence of antidepressant intake was analyzed in an effort to determine which patients were at increased risk of developing xerostomia, orthostatic hypotension or both, as well as experiencing interactions with other medications. HISTORY AND CLASSIFICATION OF ANTIDEPRESSANTS

Monoamine oxidase inhibitors. The antidepressants originated in the early 1950s with the development of the monoamine oxidase inhibitors, or MAOIs, which inhibit the action of monamine oxidase, or MAO, an enzyme responsible for the breakdown of various neurotransmitters including serotonin and norepinephrine. Inhibition of MAO is thought to relieve depression by allowing the accumulation of serotonin and norepinephrine in the presynaptic junction.47 MAOIs require restriction of tyramine intake and exclusion of other drugs with serotoninpotentiating activity. In addition, they can react strongly with opioids (especially meperidine) and sympathomimetic amines such as phenylephrine, which is commonly found in cold formulas. Noncompliance with dietary and drug restrictions may cause a life-threatening hypertensive crisis.48 Tricyclic antidepressants. In the late 1950s, introduction of the first-generation tricyclic antidepressants, or TCAs, greatly reduced the use of MAOIs in the treatment of depression. During the 1960s, the TCAs represented the major antidepressant medications used in the United States. Their effectiveness is believed to be related to an increase in the neurotransmitters serotonin and norepinephrine in the synapse.49 TCAs block central histaminergic, peripheral cholinergic and α1-adrenergic receptor 72

sites, which results in adverse effects such as xerostomia, drowsiness and orthostatic hypotension.50 The tricyclics were followed by the development of second-generation tetracyclic antidepressants. Selective serotonin reuptake inhibitors. Although successful in the treatment of depression, the traditional TCAs had significant anticholinergic and cardiovascular adverse effects. This helped focus research efforts on the development of antidepressants with fewer side effects. In the 1970s, the antidepressant fluoxetine was marketed, followed by other selective serotonin reuptake inhibitors, or SSRIs. The SSRIs block serotonin reuptake by brain neurons, making the neurotransmitter available to synaptic receptors.51 They cause less weight gain and have fewer severe cardiovascular effects than do the TCAs. Atypical antidepressants. The atypical antidepressants were introduced in the 1980s and 1990s. These include trazodone and nefazodone.51 Nefazodone, a third-generation antidepressant, was introduced in the early 1990s and is reported to have two actions on the serotonin system. These include a moderate serotonin selective reuptake inhibition and direct antagonism at the 5-hydroxytryptamine2A, or 5-HT2A, receptor. Trazodone also blocks α1-adrenergic receptors and H1 histamine receptors.52 Another atypical antidepressant is bupropion, which is a selective norepinephrine and dopamine reuptake inhibitor that has no direct action on the serotonin system.53 Bupropion acts mainly on the dopamine system and has 20 times more activity on dopamine reuptake than on serotonin reuptake. During the last decade, other new thirdgeneration antidepressants became available. These include venlafaxine, a nontricyclic antidepressant that is a dual serotonin and norepinephrine reuptake inhibitor. Venlafaxine also has a weak dopamine reuptake effect reportedly without α1-adrenergic, cholinergic and histamine receptor-blocking properties.53 Mirtazapine is another recently marketed antidepressant that, in addition to blocking serotonin receptors, has presynaptic α2-adrenergic receptor antagonistic effects that may result in an increased release of norepinephrine.54 It also is a potent histamine H1 receptor antagonist. Table 1 shows the classes of antidepressants, selected mechanisms of action and adverse effect profiles.55-59

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TABLE 1

SELECTED MECHANISMS OF ACTION AND ADVERSE EFFECTS OF ANTIDEPRESSANTS. DRUG

TRANSMITTER UPTAKE BLOCKING Serotonin

Norepinephrine

MAJOR ADVERSE EFFECTS Anticholinergic

Sedation

Xerostomia

Cardiac

Orthostatic Hypotension

MAOIs* Phenelzine

+†

0†

0

+

+

++†

+

Tranylcypromine

+

0

0

+

+

++

0

Amitriptyline

++++†

++

++++

++++

++++

+++†

++

Clomipramine

+++++†

++

+++

+++

+++

+++

++

Desipramine

++

++++

+

+

+

++

++

Doxepine

++

+

++

+++

+++

+++

++

++++

++

++

++

++

+++

+++

Nortriptyline

+++

++

+

++

+

++

+

Protriptyline

++

++++

+++

+

+++

+++

+

+

+

++

+++

++

+++

++

Amoxapine

++

+++

+++

++

+++

++

+

Maprotiline

0/+†

+++

++

++

++

++

+

Citalopram

++++

0/+

0/+

0/+

+

0

0/+

Fluoxetine

+++++

0/+

0/+

0/+

+

0

0/+

0/+

0/+

0/+

0/+

+

0

++

Paroxetine

+++++

0/+

0/+

0/+

+

0

0/+

Sertraline

+++++

0

0

0/+

+

0

0

Bupropion¶

0/+

0/+

0

++

+

0

+

Mirtazapine

+++

+++

0

+++

++++

0

++

Nefazodone

0

+++++

0

++

+

0/+

+

Trazodone

0

+++

0/+

++++

+

0/+

++

+++

+++

0

0

+

0/+

0

TCAs ‡

Imipramine

Trimipramine TCAs (Tetracyclics)

SSRIs

§

Fluvoxamine

Atypical

Venlafaxine

* MAOIs: Monoamine oxidase inhibitors. † 0: None; +: slight; ++: moderate; +++: high; ++++: very high; +++++: highest; 0/+: none to slight. ‡ TCAs: Tricyclic antidepressants. § SSRIs: Selective serotonin reuptake inhibitors. ¶ Bupropion has significantly more effect on dopamine transport (transmitter uptake blocking) than on serotonin transport.

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MATERIALS AND METHODS

20 PATIENTS (PERCENTAGE)

18 16 14 12 10 8 6 4 2 0 20 and Younger

21-30

31-40

41-50

51-60

61-70

71-80 81 and Older

AGE (YEARS) Female

We obtained data about antidepressant treatment from a review of 1,800 records of patients undergoing dental therapy at Creighton University School of Dentistry, Omaha, Neb., from 1999 through 2000. We maintained confidentiality and protocol, as required by the Institutional Review Board for the Protection of Human Subjects. A review of the medical records revealed that 381 patients (21 percent) were receiving antidepressant therapy. These patients consisted of 265 female subjects and 116 male subjects, ranging in age from 12 through 90 years. Each record contained a “Medical Review of Systems” with documented medications. We analyzed recorded data using age, sex, drug classifications, psychiatric and/or medical histories and currently prescribed medications. Antidepressant intake was analyzed as a function of age, sex and potential for clinical complications.

Male

RESULTS Figure 1. Distribution of study population (n = 381) by sex and age.

TABLE 2

REPORTED THERAPEUTIC USES OF ANTIDEPRESSANTS. INDICATIONS FOR ANTIDEPRESSANT THERAPY

NO. (%) OF ANTIDEPRESSANTS PRESCRIBED (N = 412) 176

(42.72)

13

(3.16)

5

(1.21)

Anxiety and Panic Disorders

49

(11.89)

General Medical Conditions Cardiovascular disease, transplantations, cancer, multiple sclerosis, Parkinson’s disease

61

(14.81)

Substance Abuse Withdrawal Smoking cessation, alcohol abuse, drug abuse

19

(4.61)

4

(0.97)

Pain Neuropathy, fibromyalgia, trauma to back and spine, facial

43

(10.44)

Insomnia

42

(10.19)

Depressive Disorders Bipolar Disorders Schizophrenia

Anorexia and Weight Disorders

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The female population (n = 265) outnumbered the male population (n = 116) by 2.3 females for every male (that is, 69.6 percent vs. 30.4 percent). Patients ranged in age from 12 through 90 years and were ranked by age into eight 10-year cohorts (11 through 90 years). Figure 1 shows the percentage distribution by sex and age group. The mean age of the entire population receiving antidepressant therapy was 49.1 years. The mean age of female and male subjects was 48.8 and 49.7 years, respectively. Table 2 summarizes the indications for antidepressant therapy according to psychiatric and medical conditions, as indicated in patient records. Distribution of antidepressant medications. The 381 patients in this study reported taking a total of 412 antidepressants. Three hundred fifty-two patients (92 percent) were treated with one antidepressant and 29 patients (8 percent) were treated with two or more antidepressants. As shown in Table 3, the SSRIs were the most commonly prescribed antidepressants (rank order: sertraline, fluoxetine, paroxetine, citalopram, fluvoxamine) and represented 229 (56 percent) of all recorded antidepressants received. The TCAs accounted for 92 (22 percent) of the total number of prescribed antidepressants (amitriptyline made up 72 percent of the TCAs, or 66 [16 percent] of the 412 antidepressants in all). Other TCAs in rank order of prescription fre-

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TABLE 3

REPORTED INTAKE OF ANTIDEPRESSANTS BY NAME AND CLASSIFICATION. NO. (%) OF DRUGS PRESCRIBED (N = 412)

MAOIs* Phenelzine

2

(0.50)

Tranylcypromine

2

(0.50)

TCAs † Amitriptyline

66 (16.00)

PATIENTS (PERCENTAGE)

GENERIC DRUG NAME

12 10 8 6 4

Clomipramine

1

(0.20)

Desipramine

3

(0.70)

Doxepine

5

(1.20)

11

(2.70)

Nortriptyline

6

(1.50)

Protriptyline

0

(0)

One Medication Three Medications

Imipramine

Trimipramine

0

(0)

TCAs (Tetracyclics) Amoxapine

0

(0)

Maprotiline

0

(0)

SSRIs Citalopram

19

(4.60)

Fluoxetine

71 (17.20)

‡

Fluvoxamine

1

(0.20)

Paroxetine

59 (14.30)

Sertraline

76 (18.40)

Atypical Bupropion

28

(6.80)

4

(1.00)

Nefazodone

10

(2.40)

Trazodone

30

(7.30)

Venlafaxine

18

(4.40)

412

(100)

Mirtazapine

TOTAL

* MAOIs: Monoamine oxidase inhibitors. † TCAs: Tricyclic antidepressants. ‡ SSRIs: Selective serotonin reuptake inhibitors.

quency (after amitriptyline) were imipramine, nortriptyline, doxepin, desipramine and clomipramine. The atypical and third-generation antidepressants accounted for 90 (22 percent) of the total number of prescribed antidepressants. The MAOIs made up only 1 percent of the total (four antidepressants).

2 0

20 and 21-30 Younger

31-40

41-50

51-60

61-70 71-80 81 and Older

AGE (YEARS) Two Medications Four or More Medications

Figure 2. Patients treated with antidepressants and other medications that have xerostomic potential, according to age.

Xerostomia. One hundred sixty (42 percent) of the 381 patients reported that they were receiving treatment with a single antidepressant that had xerostomic potential. One hundred fourteen patients (30 percent) reported being treated with two xerostomic medications (consisting of antidepressants and other drugs), 65 (17 percent) with three such medications and 42 (11 percent) with four or more medications that had xerostomic potential. Therefore, 221 (58 percent) of 381 patients were being treated with two or more medications that had the adverse effect of xerostomia. Figure 2 shows the number of patients taking an antidepressant and other medications with a potential xerostomic effect. Orthostatic hypotension. Not all antidepressants potentiate orthostatic hypotension. For example, most SSRIs and venlafaxine do not (Table 1). In this study, 124 patients (32 percent) were taking antidepressants and other medications without risk of developing this adverse effect. One hundred fifty-six patients (41 percent) were being treated with one medication that produced orthostatic hypotension, 76 patients (20 percent) were being treated with two such medications and 25 patients (7 percent) were being treated with three or more such medications.

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PATIENTS (PERCENTAGE)

12 10 8 6 4 2 0 20 and 21-30 Younger

31-40

41-50

51-60

61-70

71-80

81 and Older

AGE (YEARS) None Two Medications

One Medication Three or More Medications

Figure 3. Patients treated with antidepressants, other medications or both that have the potential to cause orthostatic hypotension.

Figure 3 shows the number of patients who had been treated with antidepressants and other medications that may produce orthostatic hypotension. DISCUSSION

In this study, we found that 381 (21 percent) of the 1,800 patient dental records reviewed showed antidepressant use. This finding appears to be consistent with the reported 17 percent lifetime prevalence rate of major depressive disorder in the United States60 (although we should point out that many patients in our study received antidepressant therapy for a variety of other medical conditions). The 2.3:1 female-to-male ratio is consistent with other studies that reported an increased prevalence of antidepressant use in females compared with males.61-64 This finding may reflect differences in patient physiology, frequency of health care visits and coping methods to deal with stress. As shown in Table 2, antidepressants are used in the treatment of a wide spectrum of psychiatric and other medical disorders. In this study, all generations of antidepressants were used to treat psychiatric disorders. Of dental importance is that patients often were taking anxiolytics, 76

antipsychotics, lithium and anticonvulsants concomitantly, which can greatly intensify the risk of developing xerostomia and orthostatic hypotension. Depression can act as a comorbid factor in a number of medical conditions, including cardiovascular disease; cancer; organ transplantation; and neurological disorders such as epilepsy, Parkinson’s disease and multiple sclerosis.65-79 We found that 61 (14.81 percent) of 412 antidepressants were prescribed for general medical conditions (Table 2). In addition, we found that TCAs often were prescribed to treat neuropathic pain, insomnia or both. The high percentage of amitriptyline use (16 percent) appears to be associated with its neuropathic and sleep-inducing qualities. Amitriptyline was prescribed as adjunctive medical treatment for chronic pain disorders and syndromes such as fibromyalgia; back and spine trauma and disorders; rheumatoid arthritis; migraine; neuropathy associated with diabetes mellitus, systemic lupus erythematosis and scleroderma; and facial pain related to temporomandibular joint disorder and trigeminal neuralgia. Efficacy against chronic pain has not been reported for all antidepressants since mechanisms of action differ between the various drugs.80 Increased risk of xerostomia and hypotension exist when patients are concurrently taking pain medications such as nonsteroidal anti-inflammatory analgesic drugs, muscle relaxants, narcotic analgesics, antihistamines, bronchodilators, diuretics and other antihypertensive agents. Some subjects received second- and thirdgeneration antidepressants that had low abuse and toxicity potential for the treatment of bulimia, alcohol withdrawal symptoms and narcotic addiction, as well as an aid in smoking cessation. The third-generation antidepressants venlafaxine and mirtazapine were prescribed less frequently (4.4 percent and 1.0 percent, respectively) than were other antidepressants. The MAOIs constituted only 1 percent of the prescribed antidepressants. The study findings indicate that 257 patients (67 percent) were taking one or more orthostatic hypotensive medications associated with a reported risk of dizziness, syncope and falling.81-85 Specific medications included antipsychotics, anxiolytics/hypnotics, opioid analgesics, diuretics and other drugs with antihypertensive action. A significant number of patients were taking

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antidepressants that can interact with local anesthetics containing sympathomimetic vasoconstrictors (92 TCAs [22 percent] and four MAOIs [1 percent]). TCA intake may place the patient at increased risk of developing cardiovascular disorders, especially in depressed patients with preexisting cardiac disease, where increased risks of atrial fibrillation, atrioventricular block and ventricular tachycardia can occur.86 DENTAL MANAGEMENT AND PRECAUTIONS

We designed this study to demonstrate the multitude of interactions that occur between medicine and dentistry related to antidepressant use and adverse effects. We emphasize the following for dentists to keep in mind. The importance of taking a thorough medical and dental history with regularly recorded updates of medications prescribed. This is extremely important because of potential adverse effects and drug interactions. It is important for dentists to be knowledgeable about the medications that increase the risk of xerostomia, and the need for an intensive preventive dentistry program. This preventive care program should include patient education in maintaining home hygiene practices, increased fluid intake, fluoride applications, use of therapeutic agents that stimulate salivation, use of antimicrobial rinses and regularly scheduled dental examinations.86 Precautions related to orthostatic hypotension are important in providing proper patient care and preventing liability. Dental care for patients with orthostatic hypotension should include decreased length of dental visits, positioning the patient upright in the dental chair, avoiding sudden postural changes, using caution in prescribing medications with additional orthostatic hypotension potential and providing assistance to patients—especially those who are elderly or debilitated—as they leave the operatory. In addition, it is important for clinicians to monitor patients’ blood pressure.87 The injection of local anesthetics containing vasoconstrictors often causes an increase in blood pressure that requires careful monitoring. In addition, the dental practitioner should be aware that a rare paradoxical hypotensive reaction may occur when patients taking drugs with α1adrenergic blocking activity (for example, TCAs) are given a local anesthetic containing vasocon-

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strictor (such as epinephrine). This reaction results because epinephrine, being unable to bind to the blocked α1-receptors, instead interacts with available β2 -receptors, causing vasodilation and a resultant paradoxical hypotensive reaction. Because of potential cardiovascular adverse drug interactions between specific antidepressants (that is, TCAs and MAOIs) and sympathomimetics, we suggest that the dentist confer with the patient’s physician to review his or her medical status before prescribing certain drugs or administering local anesthetics with vasoconstrictors that contain sympathomimetics (especially epinephrine and levonordefrin).85,88 Dental precautions include using a minimal quantity of local anesthetic with sympathomimetic vasoconstrictor and taking care to prevent intravascular injection. Use of epinephrine containing retraction cord or hemostatic agents is contraindicated. In patients with serious cardiac dysrhythmias, a local anesthetic without vasoconstrictor may be indicated. In addition, dentists should routinely monitor blood pressure and other vital signs.89 CONCLUSION

In this study, we found that a significant number of patients (381 [21 percent] of 1,800) were receiving antidepressant therapy for diverse medical conditions. This is important information for dental practice because of the potential for adverse effects, including xerostomia, orthostatic hypotension and interaction with vasoconstrictors, as well as the possibility that these effects may be increased by other, concurrently administered, medications. Consequently, dentists must take appropriate precautions when treating these patients. ■ Dr. Keene is an associate professor of periodontics, Department of Applied Dental Medicine, Southern Illinois University, School of Dental Medicine, 2800 College Ave., Bldg. 285, Alton, Ill. 62002, e-mail “[email protected]”. Address reprint requests to Dr. Keene. Dr. Galasko is an associate professor and head, Section of Pharmacology, Department of Applied Dental Medicine, Southern Illinois University, School of Dental Medicine, Alton, Illinois. Dr. Land is a professor of fixed prosthodontics, Department of Restorative Dentistry, Southern Illinois University, School of Dental Medicine, Alton, Illinois. 1. Modigh K. Antidepressant drugs in anxiety disorders. Acta Psychiatr Scand Suppl 1987;335(76):57-74. 2. Agosti V, Stewart JW, Quitkin FM. Life satisfaction and psychosocial functioning in chronic depression: effect of acute treatment with antidepressants. J Affect Disord 1991;23(1):35-41. 3. Goldberg JF. New drugs in psychiatry. Emerg Med Clin North Am 2000;18(2):211-31. 4. Schatzberg AF. New indications for antidepressants. J Clin Psychiatry 2000;61(suppl 11):9-17.

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