J Am Board Fam Pract: first published as 10.3122/15572625-11-2-127 on 1 March 1998. Downloaded from

CLINICAL REVIEW The Pharmacologic Treatment of

Barbara A. Majeroni, MD, and Andrea Hess, PharmD

Background. Family physicians often provide the first line of treatment for patients with depression. Many effective drugs are now available for the pharmacologic treatment of depression. Methods: We searched MEDLINE from 1991-96 under the topics of depressive disorders/treatment and . Other sources were found by back-referencing from these references and from texts. Results: Although appear to be equally effective, selective reuptake inhibitors are frequently the drugs of choice because of their safety profile and less troublesome side effects. Conclusions: When prescribing antidepressant medications, the clinician must educate patients about potential side effects and about the amount of time that must be allowed for therapeutic efficacy. Drug interactions and concurrent medical conditions are important factors in the choice of an antidepressant. (J Am Board Fam Pract 1998;11:127-39.)

Depression is a common finding in primary care care physicians who are treating major depressive practice, with a 6-month prevalence of 5.8 percent disorders with . and a lifetime prevalence of 17 percent in the United States. l Detection has been discussed else­ Classes of Antidepressants where.2 Once the diagnosis has been made, the A large selection of drugs is available in the United physician must determine the optimal treatment States for the treatment of depression (fable 1). plan for each patient. In cases of mild depression, Since all are effective, selection of a drug is based alone can be effective, but in mod­ on considerations of safety, tolerability, cost, and erate to severe depression, pharmacotherapy convenience of dosing. Potential drug interactions with an antidepressant medication is indicated, and concurrent medical conditions also guide the regardless of whether the patient is referred for selection of an appropriate antidepressant. psychotherapy.3 http://www.jabfm.org/ Selective Serotonin Reuptake Inhibitors Methods In the 1990s the drugs of choice for many pa­ The authors searched MEDLINE from 1991 tients for the treatment of major depressive dis­ through 1996 using the key words "depression! order have been the selective serotonin reuptake therapy" and "antidepressive agents" and re­ inhibitors (SSRIs), , , and

viewed current pharmacology and text­ , because they have favorable safety on 24 September 2021 by guest. Protected copyright. books regarding the available antidepressants in profiles and are easy to administer.4•5 They are the United States, with attention to potential side not lethal in overdose, and patients are less likely effects, drug interactions, and special considera­ to drop out of treatment because of adverse ef­ tions in treating depressed patients who have con­ fects. Dosage titration is not usually necessary. current medical illnesses. Earlier references were , also an SSRI, has been approved obtained by back-referencing and from the au­ for use in obsessive-compulsive disorder as well thors' files. The purpose of this review is to sum­ as depression. marize clinically useful information for primary Side effects of SSRIs are generally milder than those of the older classes of antidepressants.6 Common side effects are listed in Table 2. Nau­ Submitted, revised, 29 May 1997. From the Department of Family Medicine, State Univer­ sea, common during the first week, tends to wane sity of New York at Buffalo. Address reprint requests to Bar­ as the patient develops tolerance. Fluvoxamine bara A. Majeroni, MD, Department of Family Medicine, State University of New York at Buffalo, 462 Grider St, Buf­ has side effects similar to those of the other SS­ falo, NY 14215 RIs7 except there may be less .s Because in-

Pharmacologic Treatment of Depression 127 J Am Board Fam Pract: first published as 10.3122/15572625-11-2-127 on 1 March 1998. Downloaded from

Table 1. Antidepressants Currently Available in the United States.

Generic Name Brand Name Adult Dosage124 hr Interval Cost $*

Selective serotonin reuptake inhibitors Fluoxetine Prozac 1O-80mg qd 71-280 Paroxetine Paxil 10-50 mg qd 59-127 Sertraline Zoloft 50-200mg qd 65-133 Fluvoxamine Luvox 50-300 mg qd or bid 65-134

Tricyclic antidepressants Elavil, others 50-300 mg qd 20-106 3-14t Asendin 100-400mg qd or divided 65-260 44-176t Norpramine 50-300 mg qd or bid 25-178 14-139t Adapin 50-300 mg qd or divided 17-118 Sinequan 5-32t Tofranil, others 50-300 mg qd 24-125 2-}2t Pamelor 50-200mgqd qd or divided 59-361 Aventyl 43-260t Vivactil 15-60 mg tid or qid 45-131 37-105t Surmontil 50-300 mg divided or hs 35-154

Tetracyclic antidepressants Maprotiline Ludiomil 50-225 mg qd or divided 22-88 15-64t lvlonoamillf Oxidase Inhibitors Nardil 15-90 mg qd 13-78 Parnate 1O-40mg qd 15-60 http://www.jabfm.org/ Atypical antidepressants Wellbutrin SR 200-450mg bid 71-116 Remeron 15-45 mg qd 59-121 Serzone 200-600 mg bid 61-91 Desyrel, others 150-500 mg divided 62-335 25-65t on 24 September 2021 by guest. Protected copyright. Effexor 75-375 mg bid or tid 63-144

*Average wholesale price to pharmacist for 30-day supply at lowest to highest dosage range, rounded to the nearest dollar, from the First Databank, June 1997. Price to patient will be higher. tGeneric price when available. somnia can be a problem, these activating antide­ holidays. Short holidays are not effective with flu­ pressants are usually administered in the morn­ oxetine because it has a longer half-life. 10 Anor­ ing. Jitteriness must be differentiated from wors­ gasmia may be managed by waiting for tolerance ening , antidepressant-induced akathisia, to develop, dosage reduction, treatment with the nocturnal myoclonus, and or . , II or Management includes waiting for tolerance to prescribing a different antidepressant, such as develop, dosage reduction, and changing anti de­ bupropion. pressants.9 Patients taking sertraline and paroxe­ Drug interactions with SSRIs are listed in tine might experience considerable improvement Table 3. The combination of SSRls with mono­ in sexual function with scheduled weekend drug oxidase inhibitors (MAOIs) has resulted in

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Table 2. Common Side Effects and Frequency of Selective Serotonin Reuptake Inhibitors.

Fluoxetine Sertraline Paroxetine (Prozac) Percent*' (Zoloft) Percent*' (Paxil) Percent*'

Nausea 21 Nausea 26 Nausea 26 20 Headache 20 23 Nervousness 15 Diarrhealloose stools 18 Dry Mouth 18 14 Insomnia 16 Headache 18 Diarrhea 12 Dry Mouth 16 Asthenia 15 Drowsiness 12 Male 15 14 (ejaculatory delay) Anxiety 9 Somnolence 13 13 Anorexia 9 Dizziness 12 Insomnia 13 Increased sweating 8 11 Ejaculatory disturbance 13 11 Discontinued (side effects) 15 Discontinued (side effects) 15 Discontinued (side effects) 21

*Rounded to the nearest 1%. many adverse events, including the serotonin syn­ half-life of 146 hours (range 77 to 235 hours). It is drome, which is characterized by such mental sta­ necessary to wait at least 5 weeks between discon­ tus changes as hypomania and confusion, and tinuing fluoxetine and starting an MAOI and at physical symptoms, such as myoclonus, hyperten­ least 14 days for other SSRIs. sion, tremor, and diarrhea. 12 Death has resulted SSRIs are also prescribed for obsessive-com­ in some cases.13 SSRIs inhibit the cytochrome P- pulsive disorder, panic disorder, and premenstrual 450 2D6 and other enzyme systems in the liver, syndrome. Fluoxetine is the only SSRI available in resulting in altered metabolism of a number of liquid form. Although SSRIs cost more than many other drugs. Paroxetine and fluoxetine are the older antidepressants, drugs are only a small part most potent inhibitors. Sertraline is less active. of the cost of treating depression. An overall re­ Desipramine, nortriptyline, and venlafaxine are duction in direct cost has been shown with the also substrates of cytochrome P-450 2D6.14 Flu­ SSRIs compared with antidepressants.22 oxetine is also a potent inhibitor of the cy­ tochrome P-450 2C9 enzyme system and has Mixed Serotonin- Inhibitors http://www.jabfm.org/ been reported to block analgesia from opiates, Tricyclic antidepressants (TCAs) are the most such as morphine.1S Significantly increased half­ studied class of antidepressants because they have lives of tricyclic antidepressants,16 ,17 been in use longer. TCAs and SSRIs are equiva­ ,18 alprazolam,19 diazepam,20 and lent in efficacy for the treatment of major depres­ haloperidoPl have been reported when these sion. A list of common side effects of TCAs is

drugs are given concurrently with SSRIs. Lower found in Table 4. effects, weight on 24 September 2021 by guest. Protected copyright. doses of the affected agent might be required. Al­ gain, sedation, and are though the cytochrome P-450 3A3/4 enzyme sys­ most troubling with the tertiary amine tricyclic tem is inhibited by SSRIs, their potency is much medications, which include amitriptyline, clomip­ less than that of ketoconazole, itraconazole, and ramine, doxepin, imipramine, and trimipramine. erythromycin. Fluvoxamine is contraindicated The secondary amine tricyclic medications­ with (Seldane) and (His­ amoxapine, desipramine, maprotiline, nortripty­ mana I) and should be avoided with clozapine and line, and protriptyline--cause less sedation and . fewer anticholinergic effects. The most. important difference among the • TCAs are toxic in overdose, and patients at risk three SSRIs lies in their . Fluox­ for suicide must be given limited amounts to avoid etine has a significantly longer half-life, 84 hours, the potential for suicide. A potentially lethal TCA compared with 21 hours for paroxetine and 26 dose for an adult is only three to five times the hours for sertraline. Fluoxetine also has an active therapeutic dose, or a I-week supply of the anti­ metabolite, norfluoxetine, that has an elimination depressant. For a child the toxic dose is far less.

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Table 3. Drug Interactions With Selective Serotonin Reuptake Inhibitors.

Drug Interaction Response

Contraindicated MAOIs Potentially fatal serotonin syndrome Do not use Terfenadine (Seldane) Possible cardiovascular toxicity . Avoid Use with Cilution Class I antiarrhythmics Increase levels of antiarrhythmics Might require lower dose of , flecainide antiarrhythmic Antidepressants SSRI may increase levels ofTCAs Use lower doses and trazodone Increased half-life of some Monitor sedation benzodiazepines Decreased effect of buspirone Increase buspirone or change Carbamazepine Increased half-life of carbamazepine Monitor carbamazepine level Increased levels of SSRI Might need lower dose of SSRI Clozapine Increases clozapine effects and toxicity Lower clozapine dose Coumadin Increased prothrombin time Monitor APTf Hallucinations Avoid Digoxin Increased digoxin levels Monitor digoxin levels Increased half-life of haloperidol Monitor symptoms Phenobarbital Decreased levels of SSRI Increase dose of SSRI Phenytoin Decreased levels ofSSRI Increase dose of SSRI Tolbutamide Increased levels of tolbutamide Monitor glucose (Ultram) Possible Avoid Agitation, restlessness, GI toxicity Avoid

MAOI - monoamine oxidase inhibitor, SSRl - selective serotonin , TeA - , APTT ~ activated partial thromboplastin time, GI - gastrointestinal.

Signs of toxicity include coma, , arrhyth­ normal ejaculation or orgasm.26 Because dose-re­ mias, tachycardia, hypotension, and confusion.23 lated sustained diastolic has been re­

When TCAs are prescribed with other medica­ ported, this drug is usually reserved for patients http://www.jabfm.org/ tions, patients must be monitored for signs of unresponsive to first-line antidepressantsP Ven- ' toxicity as a result of increased levels of drug. lafaxine is a substrate of the cytochrome P-450 Reported drug interactions are listed in Tables 5 2D6 system. Such drugs as and SSRIs and 6. TCAs are contraindicated with monoamine can increase serum concentration of venlafaxine. oxidase inhibitors and should be used with caution Cimetidine reduces clearance of venlafaxine. with a number of other drugs, including class I an­ tiarrhythmic medications, such as quinidine, fle­ Mixed Serotonin Effects on 24 September 2021 by guest. Protected copyright. cainide, and propafenone. Trazodone was the first antidepressant developed TCAs are also prescribed for chronic pain, fi­ that was not lethal when overdosed. It is very se­ bromyalgia, chronic fatigue syndrome24,25 and at­ dating, which can be beneficial for patients suffer­ tention deficit hyperactivity disorder in children. ing from insomnia caused by their depression, and Amitriptyline and imipramine can be adminis­ is sometimes used along with an SSRI in patients tered intramuscularly. Doxepin and nortriptyline who have difficulty sleeping.28 Jt has fewer anti­ are available in oral solutions. side effects than many of the tricyclic Venlafaxine is reported to be effective in treat­ antidepressants, but it can cause postural hypoten­ ing severe, melancholic depression that has been sion, especiaIly in the elderly, and it has been asso­ unresponsive to other agents. Common side ef­ ciated with in a small percentage of men fects include nausea (37 percent), somnolence (23 and with arrhythmias in those with preexisting percent), dry mouth (22 perceni:), dizziness (19 heart disease. Increases in serum levels of digoxin percent), constipation (15 percent), nervousness and phenytoin have been reported when these (13 percent), asthenia, sweating, tremor, and ab- drugs are given with trazodone.29

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Table 4. Tricyclic and Antidepressants Grouped According to Frequency of Side Effects. Common Intermediate Low Not Reported

Anticholinergic effects Amitriptyline Protriptyline Desipramine Doxepin Amoxapine Nortriptyline Imipramine Maprotiline .Trimipramine Sedation Amitriptyline Amoxapine Desipramine Doxepin Protriptyline Imipramine Trimipramine Maprotiline Insomnia!Agitation Amoxapine Protriptyline Amitriptyline Imipramine Doxepin Desipramine Nortriptyline Trimipramine Maprotiline Orthostatic hypotension Amitriptyline Desipramine Maprotiline Imipramine Doxepin Nortriptyline Protriptyline Trimipramine Maprotiline Amoxapine Cardiac arrhythmias Amitriptyline Desipramine Maprotiline Amoxapine Doxepin Imipramine Nortriptyline Protriptyline Trimipramine Weight gain (> 6 kg) Amitriptyline Maprotiline Amoxapine Protriptyline Doxepin Desipramine Imipramine Nortriptyline Trimipramine

Sexual dysfunction Amitriptyline Desipramine Doxepin Nortriptyline Imipramine Protriptyline Trimipramine http://www.jabfm.org/ Nefazodone is chemically related to tra­ Mixed Norepinephrine- Reuptake Inhibitors zodone, but appears to have a more favorable The effectiveness of bupropion in the treatment side-effect profile30 It differs from the SSRIs in . of depression is similar to that of the SSRIs and that sexual dysfunction is not reported. a-Adren­ TCAs, and its efficacy has been shown in patients ergic activity is only slight, and there is virtually previously unresponsive to TeAs. Bupropion

no cardiotoxicity. Anticholinergic activity and has recently been approved for use as an aid in on 24 September 2021 by guest. Protected copyright. activity are less than with other an­ cessation.34 tidepressants. 31 Side effects include somnolence, Causing little orthostatic hypotension and no dizziness, dry mouth, nausea, constipation, head­ anticholinergic effects or sexual dysfunction, ache, and amblyopia. 32 Nefazodone is a potent bupropion appears to be safe in patients with inhibitor of the cytochrome P-4S0 3A4 isoen­ preexisting heart disease.35 Side effects can in­ zymes and is contraindicated with terfenadine clude agitation and insomnia, , confu­ (Seldane), astemizole (Hismanal), MAOIs (Nar­ sion, and weight loss. Although not lethal in dil, Parnate), and cisapride (Propulsid). If coad­ Olr'erdose, bupropion might lower the seizure ministered with triazolam or alprazolam, the threshold,36 and is contraindicated in patients doses might need to be reduced. with seizure disorders. At least 14 days should Lorazepam does not appear to be affected. Other elapse from the discontinuation of an MAOI be­ cytochrome P-4S0 substrates that might be fore initiating treatment with bupropion. Bupro­ affected include calcium channel blockers and pion should be used with extreme caution in pa­ tamoxifen.33 tients taking levodopa.

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Table 5: Interactions With Monoamine Oxidase Inhibitors. Food* Drugs Adverse Effects

Aged cheeses (Boursault, Brie, Camembert, Antidepressants (TCAs, SSRIs); levodopa; Hypertensive crisis; Cheddar, Emmenthaler, Gruyere, mozzarella, ; sympathomimetics (eg, arrhythmias; severe Parmesan, Romano, Roquefort, and Stilton); , , , headache; death beer, red wine; broad beans; caviar, anchovies; , , chicken or beefliver; smoked meats (bologna, ) pepperoni, salami, summer sausage); yeast products CNS depressants, including anesthetic Hypotension agents, meperidine, morphine, barbiturates, codeine Thiazide diuretics Can potentiate hypotensive effect Hypotension and increased extrapyramidal effects Insulin Increased hypoglycemic reactions

"Foods containing tyramine and other , often as a result of aging or fermenting.

Monoamine Oxidase Inhibitors increased appetite, weight gain, dizziness, dry Despite being effective antidepressants, the mono­ mouth, and constipation. There have been rare amine oxidase inhibitors (MAO Is) phenelzine and reports of and neutropenia.39 tranylcypromine are infrequently used because of the risk of toxic interactions with many foods and Miscellaneous drugs (Table 5). Foods containing high levels of Maprotiline, a tetracyclic antidepressant, blocks tyramine, such as aged cheeses, the brine from reuptake of norepinephrine at the neuronal mem­ pickled herring, beers, wine, liver, yeast extract, brane. Side effects (Table 4) include dizziness, dry sausages, and fava beans, can lead to a hyper­ drowsiness, , orthostatic hypotension, tensive crisis. Excessive amounts of and electrocardiographic changes, tachycardia, dys­ chocolate should be avoided. MAOIs prolong and rhythmias, blurred vision, constipation, paralytic potentiate the effects of sympathomimetic amines, ileus, hepatitis, urinary retention, and agranulocy­ http://www.jabfm.org/ which are found in many over-the-counter cold tosis. It is contraindicated in patients who have preparations. Concurrent administration can re­ had recent myocardial infarction, concurrent use sult in extreme hypertension, cerebrovascular ac­ of MAOIs, or seizure disorder. The risk of sei­ cidents, pulmonary edema, atrial and ventricular zures is increased when maprotiline is given with arrhythmias, and headacheY MAOIs are contra­ phenothiazines, when doses of benzodiazepines indicated in patients with pheochromocytoma, are rapidly tapered, and when recommended dos­ congestive heart failure. and liver disease. Patients ages of maprotiline are exceeded. Anticholinergic on 24 September 2021 by guest. Protected copyright. who are treated with MAOIs must be carefully se­ and sympathomimetic agents should be used with lected for their ability to comply with dietary caution because of additive -like effects. restrictions and refrain from taking any over­ the-counter medications38 (eg, pseudoephedrine, Adjunct Therapy phenylephrine, and so on) without specific ap­ Patients with incomplete response to a single anti­ proval from the physician. depressant or who are unable to tolerate adequate doses because of side effects might benefit from a rAdrenergic Antagonists combined treatment. An example would be using Mirtazapine is structurally unrelated to other an­ a low-dose TCA or trazodone along with an tidepressants available in the United States. It ap­ SSRI.40 has also been reported pears to be an effective antidepressive agent, but to increase the efficacy of antidepressants in some published data are weak. Transient somnolence patients regardless of preexisting thyroid status.41 occurred in more than 50 percent of patients in Low doses are used because of an increased risk of US trials. Other common side effects include osteoporosis in patients on high doses of thyrox-

132 ]ABFP March-April 1998 Vol. 11 No.2 J Am Board Fam Pract: first published as 10.3122/15572625-11-2-127 on 1 March 1998. Downloaded from ine. Although more commonly prescribed for Table 6. Drugs That Increase and Decrease the Effects , is also used in of Tricyclic Antidepressants (TCAs). unipolar depression, either alone or with another Increase TCA Levels Decrease TCA Levels antidepressant medication.42 Careful monitoring of lithium levels, electrolytes, and thyroid func­ (H2) Barbiturates tion is necessary.43 Some potential side effects in­ 13-Blockers Benzodiazepines clude drowsiness, difficulty concentrating, tremor, Diltiazem Carbamazepine increased thirst, weight gain, diarrhea, and euthy­ Estrogens Rifampin roid goiter.44,45 Indomethacin and some other Oral contraceptives nonsteroidal anti-inflammatory drugs have been 46 reported to increase lithium levels. Gastroin­ Propafenone testinal illness with vomiting and diarrhea can in­ Propoxyphene crease lithium levels. Toxic effects of lithium are Quinidine potentiated by calcium channel blockers, (eg, ver­ Selective serotonin reuptake inhibitors apamil and diltiazem), diuretics, angiotensin-con­ Verapamil verting enzyme inhibitors, and , such as carbamazepine and phenytoinY

General Prescribing Guidelines year for patients with a second episode. If the pa­ A major cause of treatment failure in depression is tient has responded, and symptoms are resolved, patient noncompliance. One study reported that the decision can be made whether to taper the pa­ 60 percent of patients in primary care stopped tient off of the drug or continue maintenance treatment within 3 weeks.48 Careful attention to therapy. In a National Institute of Mental Health patient education can improve compliance with Collaborative Depression Study, one third of pa­ the medication regimen. Because all of the antide­ tients became ill again 1 year after recovery from pressants have side effects, patients must be care­ an index episode of depression; almost one half fully informed about what to expect. Some side ef­ became ill again by 2 years; and almost three quar­ fects, such as nausea or sedation, can be transient. ters by 8 years.50 Maintenance therapy may be If patients are so informed, they might be able to continued indefinitely for patients with a history accept some discomfort knowing that they are of frequent or multiple episodes of depression, likely to develop tolerance in 1 or 2 weeks. Other major depression with preexisting http://www.jabfm.org/ side effects can be life threatening, and it is impor­ (double depression), onset of depression after the tant for patients to know which side effects must age of 60 years, long duration of individual epi­ be reported to the physician. sodes, severe index episode, poor symptom con­ Giving patients realistic expectations about the trol during continuation therapy, and comorbid of the medication also helps en­ anxiety disorder or substance abuse. A strong fam­ courage compliance. Physicians should emphasize ily history of affective disorder also increases the on 24 September 2021 by guest. Protected copyright. that (1) the patient might not notice any improve­ risk of recurrence. Maintenance therapy with full ment for several weeks, (2) these medications doses of antidepressants is highly correlated with might require up to 8 weeks for a full therapeutic preventing recurrences for up to 5 years. 51 response,49 and (3) antidepressants are effective only when taken continuously. Frequent office "ben to Refer to a Psychiatrist visits during early treatment help reduce the num­ Although many depressed patients can be ade­ ber of patients who stop their medication because quately cared for and monitored by the family they feel it is not helping when, in fact, they might physician, some patients clearly need to be under not have reached therapeutic levels. the care of a psychiatrist. Patients whose depres­ sion is severe or recurrent or who have suicidal Duration of Antidepressant Therapy tendencies, symptoms of bipolar disorder, or de­ Pharmacologic treatment should last for a mini­ pression with psychotic features (delusions, hal­ mum of 6 months after an initial episode. Most lucinations, loss of contact with reality) should be clinicians will continue treatment for at least 1 examined by a psychiatrist. Patients who fail to

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Table 7. Effects of and Recommendations for Drugs That Interact With Tricyclic Antidepressants. Drug Effect Recommendation

Antiarrhythmics Oass I: increased cardiotoxicity Avoid or use lower doses Androgens CNS effects, paranoia Avoid Decreased antihypertensive effect Increase clonidine or change medication Disulfiram Acute organic brain syndrome Avoid Decreased antihypertensive effect Increase dose or change medication Decreased antihypertensive effect Increase dose or change medication Hydantoins Increased toxicity of hydantoin Avoid Levodopa Sympathetic hyperactivity Monitor symptoms Lithium Neurotoxicity, psychotic symptoms Monitor symptoms MAOis Hyperpyrexia, muscular rigidity Contraindicated Increased blood pressure, convulsions Sympathomimetics Increased a- effects of Monitor symptoms direct acting sympathomimetics Decreased effects of mixed-acting sympathomimetics Sulfonylureas Increased effect of sulfonylurea Monitor for hypoglycemia

respond to treatment will also benefit from psy­ recommended for patients with cirrhosis. chiatric evaluation. Alternative therapy, such as Renal impairment lowers the clearance of flu­ electroconvulsive shock therapy, can be safely ad­ oxetine, norfluoxetin (its active metabolite), bu­ ministered by a competent psychiatrist. In con­ propion, and venlafaxine. Starting with lower vincing the patient to see a psychiatrist, it is help­ doses and gradually titrating to effect is the safest ful for the family physician to assure the patient course for these patients. of maintaining contact with both the patient and Patients who have cardiovascular disease are the psychiatrist. Continued contact avoids the vulnerable to drug effects and drug interactions. patient feeling that he or she is being dumped TCAs, even at therapeutic doses, have been shown and keeps the family physician aware of medica­ to slow conduction through the AV node.53 Effects tion changes that can affect the patient's medical appear to be more common in the elderly and in treatment. those with preexisting heart disease. Patients with . http://www.jabfm.org/ bundle branch block are at increased risk for con­ Treating Depression in the Medically III Patient duction disturbances caused by TCAs.54 TCAs Medically ill populations have an increased preva­ block the antihypertensive effects of clonidine, lence of major depression, reported from 20 to 40 , , guanethidine, , percent. Many medical conditions can affect the and , and can potentiate the effect of pra­

metabolism of antidepressants, some antidepres­ zosin. In patients with congestive heart failure, on 24 September 2021 by guest. Protected copyright. sants have negative effects on certain illnesses, and TCAs can cause severe orthostatic hypotension as some other medications can increase or decrease a result of

134 JABFP March-April1998 Vol. 11 No.2 J Am Board Fam Pract: first published as 10.3122/15572625-11-2-127 on 1 March 1998. Downloaded from nortriptyline is preferred, as it will cause less seda­ Patients who are agitated might benefit from tion and fewer anticholinergic effects. 58 more sedating antidepressants, such as trazodone Diabetic patients can have increased sensitivity or nefazodone. In some patients sedation will to insulin and oral hypoglycemic medications further reduce mentation. MAOIs can be useful when their depression is treated with MAOIs at in patients who are institutionalized to control low doses and increased insulin resistance when their diets and medications. Bupropion and ven­ treated at higher doses. Tricyclic antidepressants lafaxine have less-adverse effects on cognition can provide some relief from the pain of diabetic but must be prescribed with caution because of neuropathy, although other classes of antidepres­ the potential for agitation.63 sants do not.59 SSRIs can alter glycemic control. Treating depression secondary to alcoholism Patients should be carefully monitored for hypo­ can reduce the risk of relapse in patients with ma­ glycemia or hyperglycemia when antidepressant jor depression that is diagnosed after 1 week or therapy is started. longer of abstinence.64 Antidepressant treatment Amoxapine should not be prescribed for pa­ does not reduce relapse rates in patients who are tients with Parkinson disease; it has a metabolite not depressed. that has potent dopamine receptor blocking activ­ Patients with narrow-angle glaucoma should ity. , which is frequently prescribed for not be treated with drugs that have anticholinergic Parkinson patients, is a selective MAO-B in­ effects, such as tricyclic antidepressants. hibitor. Patients taking selegiline should not also Obese patients might respond better to bupro­ take SSRIs or TCAs because of the potential for pion, an SSRI, or venlafaxine, as these drugs do serious interactions.6o For patients not taking not cause the weight gain that is associated with selegiline, effective agents include imipramine, other antidepressants. nortriptyline, desipramine, and bupropion. Bu­ propion is weakly dopaminergic and might also Treating Depression in the Elderly beneficially affect the movement disorder. Ami­ Depression is the most common emotional disor­ triptyline is useful for patients who have sleeping der in the patients older than 65 years and is asso­ difficulties and excessive salivation.61 . ciated with a higher risk of death from suicide Depressed cancer patients can be helped by than for any other age group.65 Elderly patients TCAs, which can increase appetite in anorectic must be monitored more carefully because their patients, but susceptibility to side effects in this altered can cause therapeutic population limits usefulness. Nausea and weight failure from undertreatment or toxicity from http://www.jabfm.org/ loss, which are common side effects of the SSRIs overtreatment. The SSRIs are well tolerated in and bupropion, are undesirable in this population. this group, and patients are less likely to stop tak­ Venlafaxine or nefazodone might be reasonable ing them because of untoward side effects.66 Nor­ alternatives. MAOIs are contraindicated with me­ triptyline also provides effective treatment and has peridine and must be prescribed cautiously with fewer side effects in this age group than other tri­ 67 other pain medications. cyclic medications. on 24 September 2021 by guest. Protected copyright. Some demented patients are also depressed, Elderly patients should be started at lower and appropriate treatment will improve their doses than younger adults. The usefulness of quality of life. Prevalence of depression has been TCAs is limited by anticholinergic effects and se­ reported as high as 20 to 30 percent among de­ dation. Among the TCAs, desipramine is less anti­ mentia patients. There is no unique symptom or cholinergic, but can be too activating for some pa­ profile to differentiate from masked tients. Orthostatic hypotension increases the risk depression, as both have similar features, particu­ of falls and hip fractures.68 larly in the elderly. (Dementia of depression is • Trazodone, which can cause orthostatic hy­ cognitive impairments associated with depres­ potension and worsen cardiac arrhythmias, is sion that resolve with treatment of the depres­ sometimes used to promote sleep by administer­ sion.62) Formal psychometric testing might be ing it in low doses at bedtime along with a more helpful. True dementia will not improve with the activating drug during the day.69 Most elderly pa­ treatment of depression, but the depressive tients cannot tolerate doses of trazodone large symptoms will. enough to treat depression.

Pharmacologic Treatment of Depression 135 J Am Board Fam Pract: first published as 10.3122/15572625-11-2-127 on 1 March 1998. Downloaded from

Pediatric Patients tient treatment for severe depression might be Childhood depression has been treated with in­ preferable to antidepressant therapy, and elec­ tensive psychotherapyJo In a meta-analysis of troconvulsive therapy has been used safely dur­ antidepressant medication outcome studies that ing pregnancy.?5,76 involved children and adolescents, open-label A recent meta-analysis of studies evaluating studies showed efficacy, but blinded studies serum levels in nursing infants whose mothers showed no difference from .71 Hetero­ were taking antidepressants reported adverse ef­ cyclic antidepressants are metabolized more fects on infants whose mothers were treated with quickly in adolescents than in adults and more doxepin and fluoxetine. Of studied antidepres­ quickly still in younger children. Plasma levels sants available in the United States, amitriptyline, should be monitored. Rapid hepatic metabolism nortriptyline, desipramine, , and of serotonergic parent compounds, such as imip­ sertraline had no reported adverse effects on nurs­ ramine and amitriptyline, results in noradrenergic ing infants.77 active metabolites, shifting the ratio of noradren­ ergic to serotonergic activity higher than that in Concurrent Psychiatric Diagnoses adults. This shift is important because the nora­ If there is more than one psychiatric diagnosis, the drenergic system does not fully develop both choice of antidepressant must be carefully consid­ anatomically and functionally until early adult­ ered. History of a manic or hypomanic episode in­ hood.72 dicates bipolar disorder, and antidepressants must Because there have been reports of sudden car­ be used with caution because of the danger of in­ diac death, a baseline electrocardiogram and peri­ ducing a manic state. Lithium and anticonvulsants, odic electrocardiographic monitoring are recom­ such as carbamazepine and valproate, are some­ mended if these drugs are used in children. times effective alone or with an antidepressant. Prolongation of the PR interval or increased blood SSRIs and tricyclic antidepressants are effec­ pressure are indications to reduce the dose or dis­ tive in patients with major depressive disorder and continue the medicationJ2 concurrent dysthymia, sometimes referred to as Generally, safety and effectiveness of other an­ double depression)S Major depression frequently tidepressants have not been established in chil­ coexists with panic disorder.79 Tricyclic antide­ dren. For the child with severe depression, a psy­ pressants are highly effective in blocking the auto­

chiatrist should be consulted. nomic expression of panic, thus facilitating a com­ http://www.jabfm.org/ prehensive rehabilitation program. Bupropion can' Pregnancy and Lactation worsen symptoms of panic disorder.so In patients Lithium is reported to be teratogenic in the first with concurrent anxiety, medications with shorter trimester.73 SSRIs, maprotiline, and bupropion half-lives should be prescribed at a lower dose and are rated pregnancy category B, which means that increased gradually; drugs with potent anticholin­ while there were no harmful effects reported in ergic side effects should be avoided.81 Concurrent animal studies, there are no reliable data on safety substance abuse, posttraumatic disorder, on 24 September 2021 by guest. Protected copyright. in humans during pregnancy. Recently published and dissociative disorders are beyond the scope of data showed that children with three or more mi­ this review. Psychotic symptoms, such as halluci­ nor structural anomalies were more commonly nations, can occur with depression as well as with . born to women exposed to fluoxetine during preg­ a coexisting psychosis and are indications for for­ nancy, and women exposed to fluoxetine during mal psychiatric evaluation. the third trimester were more likely to have pre­ mature deliveries and low-birth-weight infants.74 Conclusion Amoxapine, desipramine, imipramine, protripty­ Of the many antidepressants available, the selec­ line, the MAOIs, nefazodone, trazodone, and ven­ tive serotonin reuptake inhibitors have become lafaxine are category C medications, and amitrip­ preferred for many patients because of their tyline and nortriptyline are category D. These , safety and lower incidence of serious side effects. drugs should be used in pregnancy only when the Drug interactions must be taken into account, benefit clearly outweighs the risk, as when the and concurrent medical illnesses can affect the life of the mother and fetus are in danger. Inpa- choice of antidepressants. Patient education re-

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