Psychosomatics 39:S2-S19, June 1998
© 1998 The Academy of Psychosomatic Medine
Psychopharmacologic Treatment of Depression in the Medically Ill
Karen Beliles, M.D., and
Alan Stoudemire, M.D.
Received March 30, 1997; revised November 26, 1997; accepted January 26, 1998. From the Department of Psychiatry, Creighton and Nebraska Universities Schools of Medicine, Omaha, Nebraska; and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia. Address reprint requests to Dr. Beliles, Department of Psychiatry, Creighton/Nebraska Universities, 600 S. 42nd Street, Box 985575, Omaha, NE 68198–5575.
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ABSTRACT
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Appropriate selection of an antidepressant agent in medically ill patients requires a careful risk–benefit assessment matching the pharmacokinetic and pharmacodynamic properties of the drug being considered against the patient's physiological vulnerabilities, potential for drug interactions, and primary symptoms of the patient's depression. While in the past antidepressant drug selection was limited by the almost sole availability of the tricyclic antidepressants, newer drugs such as selective serotonin reuptake inhibitors, bupropion, and venlafaxine have vastly simplified treating depression in the medically ill. In refractory cases of depression in patients with medical illness, electroconvulsive therapy can be used with appropriate anesthetic management.
Key Words: Psychopharmacology • Literature Review • Depression • Medically Ill • Supplement • Antidepressants
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INTRODUCTION
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We provide a brief overview of the essential psychopharmacologic principles to be considered when treating depression in the medically ill. Emphasis will be placed on judicious selection of antidepressants based on side-effect profiles, avoidance of potentially toxic drug interactions, and consideration of altered psychotropic drug metabolism resulting from organ failure. Electroconvulsive therapy can be used with appropriate anesthetic management in refractory cases of depression in patients with medical illness, a subject reviewed elsewhere.1
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DIAGNOSIS OF DEPRESSION IN THE SETTING OF MEDICAL ILLNESS
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Despite the high prevalence of mental illness in primary care patients (estimates are that 25% to 33% of primary care patients have a mental disorder diagnosable on structured psychiatric interview2,3), one-third to one-half of these illnesses are not accurately diagnosed by physicians.4–6 Several studies indicate that somatization is often the primary reason for these missed diagnoses.3,6 Depression may present with primary somatic symptoms (headache, epigastric pain, insomnia) as well as with amplification of chronic medical symptoms. In addition, some patients lack the necessary psychological vocabulary and insight to verbalize their feelings of depression—a condition that has been referred to as alexithymia. In some cultures, somatic language is the principal means of communicating affective distress—a phenomenon designated as somatothymia.7,8 Both alexithymic traits and somatothymia can obscure correct diagnosis of depression. Bridges and Goldberg3 demonstrated that 95% of their study's patients with anxiety and depression were correctly diagnosed when psychological distress was the presenting complaint, whereas only 48% of the patients with psychiatric illness who presented with somatic complaints were correctly diagnosed.9
The other major considerations in diagnosing depression in the medically ill are the potential confounding effects of somatic symptoms caused by the patient's medical illness(es). Many of the common somatic symptoms of depression, such as fatigue, anorexia, insomnia, decreased mental efficiency, weight loss, and pain, can be caused by physical illness. If a clinically significant physical illness is present, the somatic symptoms directly attributable to medical illness must be relatively discounted in the diagnostic assessment and careful attention must be directed to nonsomatic symptoms. These symptoms would include unremitting and pervasive anhedonia, hopelessness, crying, guilt, low self-esteem, worthlessness, and suicidal ideation. Historical data may also help, such as a family history of depression or a personal history of prior depressive episodes.10 Biological tests for depression, such as the dexamethasone suppression test, do not as yet have acceptable rates of sensitivity to warrant their routine use in clinical settings and are often confounded by the presence of medical illness.
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GENERAL PHARMACOKINETIC CONSIDERATIONS FOR THE USE OF ANTIDEPRESSANTS IN MEDICALLY ILL PATIENTS
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Cytochrome P450 Isoenzyme IID6
The cytochrome P450 (CyP450 isoenzyme IID6 is important in the metabolism of many psychotropic agents, including the tricyclic antidepressants (TCAs), and several neuroleptics, including haloperidol, perphenazine, and thioridazine. Cytochrome P450 IID6 drug interactions become clinically important in persons who lack this isoenzyme (from 5% to 6% of Caucasians and African Americans, 1% of Asians). In the relative absence of this isoenzyme, plasma concentrations of drugs preferentially metabolized by this enzymatic route are thereby elevated. While deficiency of this isoenzyme is genetically determined, pharmacologic conversion from normal to "poor" (inhibited) metabolism is also possible (e.g., when patients are treated with CyP450 inhibitors such as quinidine). The clinical importance of antidepressant-induced inhibition of CyP450 IID6 is the risk of unexpectedly high plasma levels of other drugs metabolized by this isoenzyme. This consequence is greatest when the second drug possesses a narrow therapeutic index and thus is elevated to a toxic level. Table 111 is a partial listing of substrates and inhibitors of CyP450 isoenzymes of clinical relevance.
All selective serotonin reuptake inhibitors (SSRIs) have the capacity to inhibit the CyP450 IID6 to some extent, with paroxetine as the relatively most potent inhibitor of this group. Most studies suggest that sertraline is the least inhibitory SSRI12 of CyP450 IID6, with sertraline's primary route of metabolism being via CyP450 IIIA3/4.
Venlafaxine's in vitro potency for inhibiting the CyP450 IID6 is 2 orders of magnitude weaker than that of paroxetine and fluoxetine.13 Given its plasma concentrations at clinically effective antidepressant doses, this drug is not expected to produce any clinically relevant effect on the functional integrity of CyP450 IID6.12
Cytochrome P450 IIIA3/4
The isoenzyme CyP450 IIIA3/4 metabolizes lidocaine and nifedipine. In addition, metabolism of the antidepressant nefazodone; demethylation of the tertiary TCAs (e.g., amitriptyline, imipramine); and the metabolism of the triazolobenzodiazepines (triazolam, alprazolam, and midazolam) are governed by this enzyme. In contrast to CyP450 IID6, CyP450 IIIA3/4 is not subject to genetic variability. CyP450 IIIA3/4 is present in liver and gastrointestinal tissue. Ketoconazole, erythromycin, and cimetidine are potent pharmacologic inhibitors of CyP450 IIIA3/4.
The SSRIs can partially inhibit CyP450 IIIA3/4, but do so relatively weakly compared with their effect on CyP450 IID6. As noted earlier, CyP450 IIIA3/4 is likely the major metabolic pathway for sertraline, but CyP450 IID6 is also involved to a minor degree in sertraline's metabolism.12
Bupropion metabolism by CyP450 IIB6 interacts with only a few medications such orphenadrine and cyclophosphamide and is thus quite safe. Carbamazepine, but not valproate, induces the metabolism of bupropion and thus may lower bupropion's serum levels.14
Mirtazapine's metabolism is mediated by several CyP450 enzymes, including CyP IA2, CyP IID6, and CyP IIIA3/4. Biotransformation of mirtazapine is not principally dependent on any single P450 enzyme because each of the aforementioned enzymes has a similar affinity for the drug. The implication of in vitro studies of mirtazapine is that this drug may be less susceptible than other drugs (which are principally dependent on a single P450 enzyme for their biotransformation) to pharmacokinetic drug interactions when it is administered with an agent capable of inducing or inhibiting P450 enzymes.15 However, the clinical significance of these observations is unknown.
Space does not permit detailed discussion of various alterations in drug serum levels caused by interactions at the CyP450 isoenzyme system. Potential interactions are shown in Table 1. When medications are used that may be predicted to raise the level of a concurrently administered medication via primary or competitive enzyme inhibition, then dose reduction is the most reasonable strategy, along with closer scrutiny of serum drug levels (if reliable assays are available). Examples in patients with medical illness would include reduction of oral theophylline dose when a patient is treated with fluvoxamine (a CyP450 IA2 inhibitor), reduction of phenytoin dose when used with an SSRI, and careful monitoring of tricyclic levels when TCA-SSRI combinations are used (as for refractory depression).
Antidepressant Half-Life (T1/2)
A drug's half-life (T1/2) is the time required to achieve steady-state plasma concentration. About 4 to 5 T1/2s are necessary to achieve steady state at a constant dose or to achieve a new steady state when dosing is changed. T1/2 can also be used to estimate how long it will take to eliminate a drug from the body after discontinuation. Buproprion is offered in both an immediate-release form that has a T1/2 of 8 hours and a sustained-release (SR) form whose T1/2 averages 21 hours and thereby allows a more constant blood level and bid dosing. A steady-state plasma concentration for buproprion SR is achieved within 8 days. The SSRIs demonstrate the clinical importance of T1/2s. Fluoxetine has as its principal active metabolite, norfluoxetine, which has a T1/2 of more than 10 days. Thus, 3 to 4 weeks may be required to achieve a steady state after initiation or change of dosing. In contrast, paroxetine (T1/2: 24 hours) and sertraline (T1/2: 24 hours) may reach steady-state concentration much more rapidly, thus allowing the clinician to make dose adjustments (according to assessment of therapeutic and toxic responses) more quickly. Antidepressants with relatively short T1/2s are desirable when treating patients with medical illnesses and complex polypharmaceutical regimens. Theoretically short T1/2s allow the clinician to switch more quickly and cleanly to an alternate medication when unfavorable drug interactions are encountered. In clinical practice, however, agents such as paroxetine have withdrawal reactions upon rapid discontinuation, so tapering is advisable.
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ORGAN SYSTEM-SPECIFIC ANTIDEPRESSANT CONSIDERATIONS
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Cardiovascular Disease
TCAs in Patients With Cardiovascular Disease.
When treating patients with cardiovascular disease, clinicians must recall that TCAs have anticholinergic, antiadrenergic, and quinidine-like effects. These side effects include alterations of heart rate and rhythm, electrical conduction, blood pressure, and myocontractility.16,17 Cardiovascular side effects are rare with SSRIs, bupropion, venlafaxine, and nefazodone.18
Therapeutic-range TCA levels may cause electrocardiogram (ECG) changes in patients with preexisting conduction delays such as atrioventricular block. Patients with preexisting intraventricular conduction delays (defined as a QRS interval greater than 0.11 seconds), sick- sinus syndrome, second-degree heart block, and bifascicular heart block are at higher risk for arrhythmias.19 Patients with more benign types of heart block, such as uncomplicated left-bundle branch block, isolated left-anterior or left-posterior fascicular block, or right-bundle branch block, are at lower risk for aggravation of heart block by TCAs,20 but these patients would still require serial ECG monitoring until stable tricyclic-serum levels are achieved.
A QT interval greater than 0.44 seconds presents a relative contraindication to TCA treatment because of the increased risk for ventricular arrhythmias. A guideline for safe use of a TCA is a corrected QT interval of no more than 0.440 seconds.
Torsades de pointes is a polymorphic ventricular tachycardia that can occur in the setting of a prolonged QT interval. This arrhythmia is potentially fatal because it can lead to ventricular fibrillation and cardiac arrest. A prolonged QT interval can result from congenital abnormalities in cardiac repolarization, although it is more commonly seen as a consequence of hypokalemia or the use of Type IA antiarrhythmics such as quinidine or TCAs. Women are more susceptible than men to this arrhythmia.21 This arrhythmia may result when potent inhibitors of CyP450 IIIA3/4 (such as ketoconazole or erythromycin) are used with the nonsedating antihistamine terfenidine.
Orthostatic hypotension is a relatively common but potentially serious cardiovascular side effect of TCAs. Elderly patients and persons with cardiac disease (including conduction abnormalities and congestive heart failure) are at increased risk for developing orthostasis and other complications.22–25
Tricyclics After Myocardial Infarction.
Randomized clinical trials of prophylactic anti-arrhythmic therapy in postmyocardial infarction patients yielded the surprising finding of increased morbidity and mortality in patients on Type IC and Type IA anti-arrhythmics.26 Since tricyclics possess Type IA anti-arrhythmic properties, by extrapolation, the use of TCAs for postmyocardial infarction depression should be avoided. SSRIs, bupropion, and venlafaxine do not possess quinidine-like properties and therefore should be considered first-line drugs for postmyocardial infarction depression.26
Bupropion in Patients With Cardiovascular Disease.
Bupropion is uncommonly reported to have significant cardiovascular effects. It has some structural similarities to amphetamines and the sympathomimetic agent diethylpropion. Bupropion has minimal anticholinergic properties and minimal effects on histamine and alpha 1- and alpha 2-adrenergic receptors. It does not affect pulse rate, alter left-ventricular function, or significantly prolong cardiac conduction in patients with preexisting bundle-branch block, nor does it exacerbate preexisting ventricular arrhythmias. Rarely, bupropion-treated patients have reported symptoms of syncope, dizziness, and fainting. Syncope has been reported in 1.2% of bupropion-treated patients vs. 0.5% of placebo-treated patients.27
Roose and co-workers28 compared the cardiovascular effects of bupropion with those of imipramine in depressed patients with congestive heart failure. Neither bupropion nor imipramine adversely affected ejection fraction or other indices of left-ventricular function, but half of the imipramine-treated patients developed severe orthostatic hypotension. Bupropion may cause an elevation in blood pressure but very rarely induces orthostatic hypotension.29 It provides little, if any, sedative benefit and is, in fact, more likely to cause activation. Bupropion may induce agitation or provoke psychosis30 and therefore should not be given to patients who are prone to psychosis or have depression with psychotic features. However, if a nonpsychotic depressed patient with cardiovascular disease is hypersomnolent or subjectively anergic/easily fatigued, bupropion may be a reasonable drug choice. Bupropion may be the antidepressant least likely to induce a manic episode in bipolar patients, and some clinicians use it as a first choice in treating the depressive phase of bipolar disorder.
SSRIs in Patients With Cardiovascular Disease.
SSRIs are particularly useful in the context of cardiovascular disease because of the relative lack of quinidine-like properties and lack of effect on blood pressure (in contrast to the TCAs). Bradycardia and atrial fibrillation have been attributed to fluoxetine,31–33 but such reports are extraordinarily rare.
The newer SSRIs (e.g., sertraline, paroxetine, fluvoxamine) may also lower heart rate. There is some evidence that sertraline can induce sinus bradycardia.34 Paroxetine does not appear to have clinically significant effects on the ECG at therapeutic doses in humans.35–37 In addition, paroxetine doses of 20–40 mg/day do not appear to alter heart rate or blood pressure.
Venlafaxine in Patients With Cardiovascular Disease.
Neither venlafaxine nor its major metabolites exhibit significant binding at muscarinic, alpha-adrenergic, histaminergic, µ-opiate, or D2–dopamine receptors. Venlafaxine is similar to the SSRIs in its probabilities of sedation and activation. Studies thus far indicate that venlafaxine has minimal to no effect on cardiac conduction. However, this drug has been associated with elevations of blood pressure (incidence of greater than 5% in doses above 200 mg/day). Sustained increases in blood pressure (i.e., treatment-associated increases of diastolic blood pressure greater than 90 mmHg and greater than 10 mmHg above baseline) occur in a dose-dependent fashion, with an incidence of about 3% at doses below 100 mg/day, 5% to 7% with doses between 100 and 300 mg/day, and 13% at doses above 300 mg/day.38 Therefore, when blood pressure control is a primary concern, venlafaxine should be used only if blood pressure can be regularly monitored. No data are available on its propensity to raise blood pressure in patients with preexisting hypertension.
In medically healthy persons, venlafaxine does not produce any significant effects on the ECG. However, experience with this agent in elderly and medically ill patients is quite limited.
Trazodone and Nefazodone in Patients With Cardiovascular Disease.
The triazolopyridine antidepressants trazodone and nefazodone differ in their sedative properties. Of the two, trazodone is more antihistaminic and thus more likely to produce sedation and is also more potent as an alpha-blocking agent39 and thus more likely to cause orthostatic hypotension. Nefazodone is not totally devoid of anticholinergic, antihistaminic, or anti-alpha-adrenergic side effects; it can produce clinically significant dizziness, weakness, lightheadedness, and blurred vision. Nefazodone-treated patients have a significantly lower supine systolic blood pressure than placebo-treated subjects. However, in comparison to standard TCAs, nefazodone-related side effects are expected to be significantly less problematic. Further study of nefazodone use in the medically ill is necessary to clarify its benefits and risks in specific disease states.
Nefazodone has relatively benign effects on the ECG. It has been associated with clinically asymptomatic bradycardia, but in clinical trials drug discontinuation for this reason was rare. In premarketing drug trials, observed changes included three cases of nonspecific ST-T wave changes, two cases of extrasystoles, two cases of first-degree atrioventricular block, two cases of ST-T wave depression, two cases of bradycardia, one case of ventricular extrasystoles, one case of left-ventricular hypertrophy, one case of angina pectoris, one case of sinus arrhythmia (with occasional premature ventricular contractions and premature atrial contractions), and one case of atrial fibrillation. According to the manufacturer's information, these ECG findings were otherwise clinically insignificant and usually occurred in patients with preexisting cardiovascular disease. Modest decreases in resting pulse rate have also been attributed to nefazodone.40
Mirtazapine in Patients With Cardiovascular Disease.
Mirtazapine has a low affinity for muscarinic cholinergic receptors and for alpha-1 adrenergic receptors. Therefore, this drug produces minimal anticholinergic side effects and orthostatic hypotension. Furthermore, mirtazapine, like the SSRIs venlafaxine and nefazodone, does not inhibit fast sodium channels; therefore, it does not slow intracardiac conduction.41 In clinical trials with patients lacking heart disease, mirtazapine did not appear to affect blood pressure or the ECG. Mirtazapine had no significant effect on total peripheral resistance, stroke volume, or blood pressure. However, mirtazapine did increase heart rate 15% and decreased heart rate variability, although less so than imipramine.41 Clinical information on the use of mirtazapine in patients with cardiovascular disease is lacking.
Interactions With CyP450 IID6 in Patients With Cardiovascular Disease.
CyP450 IID6 is involved in the metabolism of beta-adrenergic blocking agents (e.g., propranolol, metoprolol); the anti-arrhythmics encainide, mexiletine, and propafenone (Type I-C); and verapamil. The CyP450 IID6 enzyme system is also important in metabolism of the TCAs. Quinidine binds to CyP450 IID6 and directly inhibits its metabolic activity. Extensive metabolizers of P450 IID6 are thereby converted to poor metabolizers by quinidine. Hence, patients on quinidine are more prone to high serum levels and adverse side effects when they concurrently receive drugs whose metabolism is primarily via P450 IID6 (see Table 1). The clinical importance of drug-induced inhibition of CyP450 IID6 is the risk of unexpectedly high plasma levels of agents normally metabolized via this route.
As discussed earlier, all SSRIs have the capacity to inhibit CyP450 IID6 to some extent. The interaction of sertraline and a single dose of the beta-blocker atenolol has been studied in a group of healthy patients42; sertraline did not influence atenolol-induced reduction of exercise heart rate. Use of beta-blockers, which undergo minimal or no hepatic biotransformation (e.g., atenolol or nadolol), may minimize potential SSRI drug interactions. From a pharmacokinetic point of view, sertraline may be the preferred SSRI for cardiovascular patients who are taking the beta-blocking agents encainide and/or mexiletine. Sertraline has no clinically important pharmacokinetic interactions with digoxin.42
Interactions Between SSRIs and Benzodiazepines.
Benzodiazepines are favored by many cardiologists for the treatment of anxiety in the setting of coexisting cardiovascular disease. SSRIs such as fluoxetine can alter metabolism of benzodiazepines such as diazepam, thereby elevating plasma benzodiazepine concentration via interference with cytochrome oxidative mechanisms. Interestingly, clonazepam metabolism is not affected by the SSRIs in this manner. Clonazepam is metabolized via nitro reduction, which produces a 7-amino metabolite.43 Extrapolation from kinetic studies of the 7-nitro benzodiazepine nitrazepam suggests that clonazepam's metabolism would not be altered significantly by aging.44,45,46 In light of these actions, clinicians should be aware of the possibility of SSRI-associated increases of benzodiazepine levels when benzodiazepines primarily metabolized via oxidation (diazepam) are used for anxiolysis and/or sedation.
Nefazodone with predominant (but not exclusive) effects on serotonin reuptake does not have any clinically significant interactions with lorazepam but may potentiate the psychomotor effects of alprazolam by increasing its serum levels. Therefore, reductions in alprazolam dose are recommended if it is to be used with nefazodone. Similar effects have been described between nefazodone and triazolam. (See Table 1.)
Protein-Binding Changes and Anticoagulant Effects.
Another type of pharmacokinetic drug interaction of potential importance involves drug-induced changes in protein binding of other drugs. The SSRIs can potentially displace the anticoagulant warfarin from protein-binding sites, thereby leaving more free warfarin available for biologic activity. Clinically, however, fluoxetine does not appear to significantly change warfarin's anticoagulant effect.46 (However, fluoxetine has been reported to increase bleeding times via dose-dependent reduction of platelet serotonin.47) In contrast to fluoxetine, both fluvoxamine and sertraline have been reported to increase prothrombin times.48,49 Although paroxetine has no reported effect on total warfarin levels, it may be associated with an increase in bleeding time when coadministered with the anticoagulant.50
Anticoagulation of a depressed patient does not preclude use of an SSRI. If an SSRI is selected for use in a cardiovascular-diseased patient who is anticoagulated, checking prothrombin time and bleeding time before any surgical procedure is recommended.40 If bleeding time is elevated, fluoxetine should be discontinued temporarily in the event of elective surgery. Abrupt discontinuation of paroxetine or sertraline in a similar situation might be more likely to produce withdrawal symptoms, since these SSRIs have shorter T1/2s than fluoxetine. If emergency surgery is necessary for an SSRI-treated patient, the clotting time might be adjusted by administration of fresh-frozen plasma or clotting factors.40
In contrast to the SSRIs, venlafaxine binds weakly to serum proteins (25%–35%). Therefore, venlafaxine is relatively less likely to induce significant changes in anticoagulant activity.
Gastrointestinal Disease
Comorbidity of gastrointestinal symptoms and psychiatric phenomena is common. For example, panic disorder often presents with gastrointestinal symptoms. Anxiety may increase swallowing rates and thus exacerbate esophageal dysmotility. Hiatal hernia may coexist with generalized anxiety and/or depressive disorders.51 Behavioral problems such as alcohol ingestion and tobacco use foster gastric, liver, and pancreatic disorders. Thus, Switz52 hypothesized that up to 60% of a gastroenterologist's clinical activities are devoted to complaints that are of psychological origin.53
TCAs in Patients With Gastrointestinal Disease.
The tertiary TCAs (e.g., amitriptyline, imipramine) provide some sedative benefit and are unlikely to activate the gastrointestinal (GI) system. Associated anticholinergic activity of these drugs may actually result in slowing of GI motility. This effect may be most significant with highly anticholinergic TCAs such as amitriptyline. Gradual increases in TCA dose and monitoring of plasma drug levels are helpful in averting this dose-related complication. However, if the patient is also being treated with cimetidine, control of TCA levels may be more difficult because of cimetidine's inhibition of the enzyme system responsible for TCA demethylation, which is described later.
Anticholinergic agents are commonly used as first-line drugs by many clinicians for treatment of functional GI distress, including irritable bowel syndrome (IBS). Studies of antidepressant use for IBS suggest that these medications can beneficially affect motility as well as discomfort. This therapeutic effect may be related to TCA's anticholinergic activity, but one controlled study suggests that benefits are independent of this activity.54,55 One of the least appreciated facts in clinical psychiatry is the usefulness of low doses of tricyclics in treating generalized anxiety disorder—a condition commonly associated with GI symptoms.
Oral Administration of TCAs in GI Disease.
Most orally administered psychotropic drugs are absorbed by the proximal ileum. Disease can alter drug absorption in various ways, including changing GI motility or pH; decreasing functional absorptive surface area (e.g., when disease necessitates surgical resection); disrupting mucosal function; or diverting blood flow to other organ systems. In general, slowed GI motility results in better absorption of poorly soluble drugs and decreased rate of extent of absorption of others. Various drugs (e.g., metoclopramide, narcotics) change gastric emptying times and thus alter rates of drug absorption. Changes in gastric pH may affect absorption of orally administered psychotropic agents. TCAs are weak bases and thus dissolve best in an acidic environment (where they are ionized but not well absorbed). Most psychotropic drugs are absorbed in the small intestine's more alkaline environment. Antacids and histamine (H2) blockers may affect TCA absorption, but there are no useful guidelines for altering drug dosage in cases of disease- or drug-altered GI pH. Likewise, there are no easily applied indices of altered drug absorption when disease reduces mucosal surface area or function. Surgical procedures (e.g., jejunoileal bypass, J-tube placement) may alter drug absorption via reduction of epithelial surface area, or alterations in motility or secretory function. Psychotropic drug absorption is minimally affected by GI disease localized to the large intestine because absorption of TCAs occurs primarily in the proximal small intestine.56
Administration with food has little effect on absorption of the TCAs, although this issue has not been extensively studied for any of these medications. Some TCAs (e.g., nortriptyline), as well as fluoxetine, are available in liquid forms (see Table 257). Solutions and elixirs are sometimes better tolerated in patients with oropharyngeal pathology, esophageal dysmotility, or nausea.
Parenteral Administration of TCAs.
Parenteral administration of TCAs may be indicated for patients who are unable to tolerate oral medications. Amitriptyline, imipramine, and clomipramine are available in injectable form. Some patients may tolerate larger oral doses of TCA when they have previously received the drug via intravenous infusion. Parenteral administration of TCA minimizes first-pass hepatic metabolism and thus enhances bioavailability of the parent compound (whose pharmacodynamic properties may be preferable in some patients to those of the active metabolites). Because of a lack of sufficient data on risks, clinicians are advised to use parenteral TCAs only when the oral route is not feasible. Therefore, each patient treated should be observed closely, with monitoring of vital signs and the ECG during and after the infusion.57
Trazodone and Nefazodone in GI Disease.
Trazodone is more sedating than the chemically related antidepressant nefazodone, and trazodone is also less likely than nefazodone to cause GI activation. Dyspepsia and abdominal pain have been associated with nefazodone; such complaints are more likely in patients with a history of peptic ulcer disease. In addition, mild dry mouth, nausea, and constipation have been attributed to nefazodone. Trazodone should not be taken on an empty stomach.
Drug Interactions in GI Disease.
Cimetidine inhibits the CyP450 isoenzyme IIIA3/4 that is present in both liver and gastrointestinal tissue. Recall that this is the enzyme system involved in metabolism of nefazodone and demethylation of tertiary TCAs such as amitriptyline and imipramine. Although there are no published data regarding the clinical significance of this potential interaction, one might postulate that concomitant use of cimetidine and one of these antidepressants could lead to drug accumulation and increased incidence of antidepressant toxicity (e.g., nefazodone-related increases in GI motility; TCA-associated anticholinergic effects with resultant decreased GI motility). In contrast to cimetidine, ranitidine does not appear to affect TCA kinetics.58 Cimetidine inhibits the metabolism of venlafaxine (clearance reduced by over 50%) but does not appear to affect desmethyl-venlafaxine in this manner.
Renal Disease
Peritoneal dialysis and hemodialysis make patients dependent both on the technology and on the persons responsible for performing the procedure. Many dialysis patients experience diminished sexual activity. Furthermore, the majority of hemodialysis patients employed prior to illness become unable to maintain full-time employment after initiation of dialysis. Thus, depressed mood and depressive syndromes occur frequently in the context of renal disease and dialysis. Evaluation of dialysis patients for depression is complicated by the fact that the signs and symptoms of renal failure and treatment side effects may be identical to vegetative signs and symptoms of depression (e.g., decreased appetite, dry mouth, constipation, low energy, easy fatiguability, and diminished sexual interest and activity).59
Pharmacokinetic Considerations in Renal Failure.
The kidneys' primary pharmacokinetic role is the elimination of drugs from the body. However, renal disease not only affects drug excretion, but may also influence absorption, distribution, and metabolism. Renal failure affects drug absorption by raising gastric pH, which is caused by ammonia buffering. Passive reabsorption of TCAs is affected by urinary pH and flow rate. Disease-induced changes of pH and urine flow are rarely clinically significant, however. When acute renal failure results from ischemia, hepatic perfusion (and thus drug distribution to the liver) may also be reduced. Uremia may cause increase capillary permeability, thus altering drug distribution.
Body water volume is generally increased in uremic patients. In these cases, larger doses of water-soluble drugs (e.g., lithium) or protein-bound drugs (e.g., most other psychotropics, including TCAs) may be required to achieve a chosen serum–drug concentration. The inverse is true for patients who are dehydrated or who have profound muscle wasting and therefore have apparent decreased volumes of distribution.
Renal blood flow may be altered by pathological vascular glomerular processes, decreased effective circulation, and disease processes affecting other organ systems (e.g., hepatorenal syndrome in liver failure and cardiac failure).
In such complex disease-induced pharmacokinetic disruptions, the simplest and most conservative approach is to reduce initial dosage and to titrate upward more slowly if chronic antidepressant therapy is indicated.56
Dialysis.
Drug removal rates by dialysis are determined by concentration gradients and are inversely proportional to molecular mass. Hemodialysis involves higher flow rates than does peritoneal dialysis; thus, solute removal is more efficient by hemodialysis. Protein binding limits the transport rate of many drugs. In general, drugs with a molecular weight of 500 Daltons or less (specifically, lithium) are removed by dialysis. Protein binding usually reduces dialyzability. Drugs that are highly protein-bound (90% of most antidepressants, with the exception of venlafaxine) are not significantly removed by dialysis. Lipid-soluble drugs (i.e., pharmacologically active psychotropic drugs) and metabolites have larger volumes of distribution and are relatively less concentrated in the blood. Thus, they are not substantially hemodialyzed from the patient.56,60,61
Dose Adjustment for Renal Failure.
Dose adjustment for renal failure generally requires that drug dosage be reduced or that the dosing interval be lengthened. In some cases, tablet fractionation is not practical, so the interval must be changed. More often, dosing is planned according to established guidelines using indicators of renal function such as creatinine clearance. Serum creatinine changes occur frequently in medically ill patients. When renal function declines, creatinine T1/2 increases. A lag time (4 to 5 T1/2s) occurs before the change in serum creatinine correctly reflects the glomerular filtration rate (GFR).62 For practical purposes, a stable serum creatinine can be assumed when two separate determinations (preferably obtained 24 hours apart) have values within 0.2 mg/dl of each other.62
TCAs in Renal Insufficiency.
Cyclic antidepressants are characterized by low renal clearances and high volumes of distribution. Their large volumes of distribution reflect significant drug penetration to tissues and predict poor dialyzability. Despite their small molecular weights, TCAs are relatively insoluble in water and are thus poorly dialyzable by conventional hemodialysis (as opposed to resin or charcoal hemoperfusion).63 Monitoring of TCA plasma concentrations is recommended for patients with kidney disease, but clinical signs of therapeutic and toxic effects are more reliable guides to dose adjustment.56
Hydroxylated TCA metabolites have been studied in patients with chronic renal failure. Lieberman et al.64 demonstrated that conjugated hydroxylated metabolites of TCAs are markedly elevated (500%–1,500%) in hemodialysis patients compared with control subjects. The hemodialysis group had less significant increases of unconjugated hydroxylated metabolites. The bioactivity of conjugated hydroxylated TCAs is not particularly well studied, but hydroxylated TCA metabolites are hypothesized culprits in production of some toxic effects. Therefore, a patient with renal failure may exhibit TCA toxicity, despite laboratory-determined serum-TCA parent-drug (and demethylated metabolite) levels in the therapeutic range.56
SSRIs in Renal Insufficiency.
The pharmacokinetics of fluoxetine and norfluoxetine are not significantly affected by mild, moderate, or severe renal dysfunction.65,66 Data for other SSRIs in renal disease are limited, but the need for major dose adjustment based on renal disease alone is unlikely.
Venlafaxine in Renal Insufficiency.
Venlafaxine's elimination half-life is prolonged by 50% and its clearance is reduced by 24% (vs. normal controls) in patients with renal disease (GFR: 10–70 ml/min). Decreased clearance of venlafaxine's principal metabolite has been demonstrated in dialysis patients. In dialysis patients, venlafaxine's T1/2 is prolonged by 189%, and its clearance is decreased by 57%. Desmethyl-venlafaxine T1/2 is increased by 40% in chronic renal failure patients (GFR: 10–70 ml/min); its clearance appears unchanged. In dialysis patients desmethyl-venlafaxine T1/2 is increased by 142%, and its clearance is reduced by 56%. The clinical significance of these changes in half-lives and clearances is not clearly established. Nevertheless, these observations indicate the wisdom of reducing initial dosage and slower dose titration for patients with renal failure, on or off dialysis. In addition, more frequent monitoring of blood pressure is good practice for patients with renal insufficiency.40
Mirtazapine in Renal Insufficiency.
Mirtazapine is eliminated predominantly (75%) via urine. Following a single 15-mg oral dose, patients with moderate GFR (11–39 ml/min/1.73/m2) and severe GFR (<10 mlL/min/1.73/m2) renal impairment had reductions in mean oral clearance of mirtazapine of about 30% and 50%, respectively, compared with normal control subjects. Therefore, mirtazapine dose reductions are recommended by the manufacturer for patients with renal disease.67
Hepatic Disease
In assessing and treating patient complaints of depression, insomnia, or hypersomnia stemming from liver disease, the clinician must carefully determine whether hepatic encephalopathy is present and whether it is contributing to reported changes in sleep. Specific treatment with lactulose or antibiotics may abrogate the need for antidepressants or sedatives. In addition, patients with hepatic encephalopathy are often more susceptible to the sedative effects of psychotropic agents. This may be particularly true of patients with subclinical encephalopathy.68 From 50% to 60% of cirrhotic patients who do not display overt features of neuropsychiatric impairment nevertheless will have subclinical or latent encephalopathy on detailed psychometric and electroencephalogram evaluation.69 Thus, despite subjective complaints of insomnia in patients with liver disease (and perhaps also a history of alcohol abuse), the less sedating antidepressants constitute a less risky initial approach to treatment.
Cognitive function should be thoroughly evaluated before initiation of antidepressant medication in patients with liver disease. Reevaluations should occur periodically thereafter to ensure that psychotropic treatment is not exacerbating cognitive difficulties. As liver disease progresses, sleep disturbances such as restlessness and middle-of-the-night awakenings may become more problematic, caused, in part, by the physical discomfort of ascites. Sleep-cycle reversal can also occur. As in any case of sleep disturbance in a medically ill patient, good sleep-hygiene practices should be encouraged before initiation of a specific sedative drug. Nevertheless, a liver-diseased patient who meets criteria of depression should receive antidepressant medication when indicated. Selection of a particular drug can then be guided by need for sedation or activation.
Protein-Binding Changes in Hepatic Disease.
Hepatic disease affects drug distribution via changes in quantities and affinities of binding proteins. The significance of these disease-induced changes in protein binding depends on two issues: 1) the resultant change in free fraction of the specific drug and 2) the drug's therapeutic index. In general, the degree of liver damage is reflected by the extent of change in drug-binding to plasma proteins. Cirrhosis tends to cause more significant change of drug-binding than does acute viral hepatitis. More extensively bound (greater than 60%) drugs, for example, the vast majority of psychotropic agents, are affected more than poorly bound drugs, for example, lithium. No practical methods are available to predict drug-binding changes that result from altered protein binding. Thus, serum-drug (bound + free) concentrations must be interpreted in the context of observed therapeutic effects and toxicity.
Ascites.
Hepatic disease also influences drug distribution via formation of ascites. Ascitic fluid contains albumin and other plasma proteins. If protein synthetic function is also compromised, ascites may reduce serum-protein concentration and protein binding of drugs. The volume of ascites is usually greater than three liters before it becomes clinically apparent. Massive ascites may exceed 20 liters. Drugs are then less confined to the vascular space; this increases their apparent volumes of distribution and decreases measured plasma or serum concentrations.56 In the presence of ascites, measured serum-plasma TCA levels might be lower than expected from a given dose. As always, the clinician must rely on assessment of therapeutic benefit and TCA-associated side effects to guide dose adjustments in patients with ascites.
Hepatic Metabolism.
Drug metabolism is often affected by liver disease, but not all metabolic pathways within the liver are equally influenced by a given disease process. On one hand, water-soluble drugs (e.g., lithium, conjugated drugs like lorazepam or their metabolites) are usually excreted by the kidney, requiring little or no modification by disease-altered hepatic metabolism. On the other hand, lipid-soluble drugs (most psychotropic drugs) are generally metabolized to more polar, water-soluble forms before elimination. Disease may characteristically affect a particular anatomic region of the liver and thereby alter some metabolic processes more than others. For example, acute viral hepatitis and alcoholic liver disease have more pronounced effects on the pericentral region, where oxidative metabolic reactions are concentrated. Therefore, these diseases may be expected to affect metabolism of most psychotropic agents (with notable exceptions, including lithium and the benzodiazepines lorazepam, oxazepam, and temazepam). In the absence of cirrhosis, chronic hepatitis predominantly affects the periportal regions, thus sparing some hepatic oxidative function.70,71 In its early stages, primary biliary cirrhosis also primarily affects periportal regions.71,72 Acute and chronic liver disease tends to spare glucuronidation reactions.72,73
TCAs in Hepatic Disease.
A drug with a narrow therapeutic margin (e.g., a TCA) is more likely to be significantly affected by changes in protein binding than is a drug with a comparatively broad therapeutic range (e.g., SSRIs). Furthermore, if the psychiatric clinician selects a highly protein-bound antidepressant (e.g., TCA, SSRI), it must be with the awareness that this may disturb the protein binding of other (nonpsychotropic) drugs being given to the patient.56
Venlafaxine in Hepatic Disease.
In contrast, venlafaxine is unique among the antidepressants in that it binds weakly to serum proteins (25%–30% bound). Therefore, venlafaxine is unlikely to disturb protein binding of other medications administered to a patient with liver disease. Venlafaxine kinetics are not expected to be disrupted significantly by liver disease–induced changes in binding proteins.
The elimination half-life of venlafaxine is increased by about one-third (30%), and its clearance is decreased by half in patients with cirrhosis (vs. normal control subjects). Similarly, the half-life of desmethyl-venlafaxine is increased by 50%, and its clearance is decreased by 30%. In severe liver disease, clearance can be reduced by as much as 90%, compared with healthy subjects.74
Venlafaxine's sedative effect may be useful in treatment of depressed patients with sleep disturbance. Recall, however, that anorexia and nausea associated with hepatic disease may be exacerbated by venlafaxine.
SSRIs in Patients With Hepatic Disease.
Average clearance rates of fluoxetine and norfluoxetine are lower, and elimination half-lives are almost doubled in patients with cirrhosis vs. healthy control subjects.65 Elimination half-lives of other SSRIs, such as paroxetine and fluvoxamine, are also prolonged in the presence of liver disease.75–77
Sertraline has rarely been reported as the cause of reversible elevations in serum glutamate oxaloacetate transaminase and alkaline phosphatase.78 Despite this minor risk, sertraline's short T1/2 (relative to fluoxetine) and less potent inhibition of P450 metabolism (relative to fluoxetine and paroxetine) may render it more preferable among the SSRIs for treatment of depression in the context of liver disease.56
Trazodone and Nefazodone in Patients With Hepatic Disease.
Trazodone is highly sedating but has relatively little anticholinergic activity. Its volume of distribution is lower than that of the TCAs; this is reflected in its longer elimination T1/2. Trazodone is excreted primarily (75%) unchanged in the urine, but some hepatic metabolism occurs.79 Prolonged clearance of trazodone from patients with compromised hepatocellular function is to be expected. Dose reduction is appropriate in these cases; however, the profound sedative effects must be considered a relative contraindication to use in encephalopathic patients.56
Mirtazapine in Patients With Hepatic Disease.
Following a single 15-mg oral dose of mirtazapine, its oral clearance was decreased by about 30% in hepatically impaired patients, compared with normal control subjects. Thus, the manufacturer recommends a dose reduction for patients with liver disease.67
Mirtazapine is a potent antagonist of histamine (H1) receptors; this property may explain its prominent sedative effect. The sedative effect of mirtazapine is a relative contraindication for patients with liver disease and the risk of hepatic encephalopathy.
Psychostimulants as Antidepressants in the Medically Ill
A well-established tradition exists in consultation-liaison psychiatry of using stimulants such as methylphenidate and occasionally dextroamphetamine to treat anergic depression in the medically ill. There is very little if any cardiovascular risk with the usual doses of these drugs when used for this purpose (e.g., methylphenidate 10–40 mg/day). Pemoline (Cylert) has been recommended for some patients with intractable nausea, vomiting, or GI disease because it can be absorbed sublingually. Bupropion, with its activating properties, theoretically might be considered as a better alternative because of its proven safety and efficacy with longer term use if patients have no risk factors for seizures.
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SPECIAL CONSIDERATIONS: SLEEP, EXTRAPYRAMIDAL SYMPTOMS, AND SEXUAL DYSFUNCTION IN MEDICAL PATIENTS
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Sleep Disturbance
Depression is usually associated with sleep disturbance, thus causing and/or exacerbating insomnia or hypersomnia. Indeed, DSM-IV criteria for major depressive episode and dysthymic disorder include disturbance of sleep (hypersomnia or insomnia).
Disturbances of sleep are common in medically ill patients, and sleep disturbance may contribute to the rationale for selection of an antidepressant drug. Many medical illnesses and medications disrupt sleep. In one series of hospitalized patients requiring psychiatric consultation, 80% had disturbed sleep.80 Whether sleep problems arise acutely as a result of medical illness(es) or as side effects of medications prescribed for nonpsychiatric reasons, they are often cited by patients or primary caregivers as important sources of distress.
Antidepressant medications vary in likelihood of causing sedation or activation. Thus, initial selection of an antidepressant drug for the depressed, medically ill patient may be influenced by desired effects on sleep. Selection of a single sedating antidepressant medication may obviate the need for further complication of a pharmaceutical regimen by use of a separate sedative drug. However, whether depression is present, good sleep-hygiene measures and simplification or modification of current medications are prudent initial approaches to treatment of sleep disturbances in medically ill patients.
Antidepressant-induced sedation may be mediated through histamine and/or alpha-adrenergic receptor antagonism, monoamine oxidase inhibition, or serotonin reuptake blockade. Accordingly, sedation is more common with TCAs (tertiary more than secondary amines), mirtazapine, and trazodone, compared with the SSRIs, venlafaxine, bupropion, and nefazodone.18,41,81,82 The sedative/activating properties of an antidepressant agent in a particular person can be manipulated by alteration of the dosing schedule. If drug-associated sedation or activation is not amenable to such schedule changes, dose reduction or a trial of an antidepressant from a different chemical class may be necessary.
Antidepressant-associated insomnia is more common with monoamine oxidase inhibitors, SSRIs, venlafaxine, and bupropion. It is relatively uncommon with most TCAs, trazodone, and nefazodone. When antidepressant-induced insomnia is suspected, the clinician must attempt to exclude worsening depression, antidepressant-induced akathisia, hypomania or mania, and nocturnal myoclonus. If antidepressant treatment results in an unwanted decrease in sleep, approaches include dose reduction, alteration of dosing schedule, waiting for tolerance to develop, or switching to another drug.18 Concurrent small doses of trazodone (i.e., 50–100 mg) are commonly used in clinical practice to improve sleep quality.
Extrapyramidal Symptoms and SSRIs
SSRIs can cause extrapyramidal side effects, including akathisia, dyskinesias, dystonias, and drug-induced parkinsonism,83–86 via antidopaminergic mechanisms. Anecdotally, extrapyramidal side effects other than akathisia are most likely to occur in the older patient. These effects may be caused by the inhibition of dopamine production resulting from increased synaptic serotonin. Inhibitory effects of serotonin and SSRIs on dopamine systems have been demonstrated in animal models.87 Some reports have indicated fluoxetine may worsen symptoms of Parkinson's disease, but other reports have either not observed this effect or minimized it.88 Akathisia, however, is a relatively common extrapyramidal symptom in patients treated with SSRIs. It is most often encountered with fluoxetine. Akathisia can be managed by dose reduction or by treatment with low doses of propranolol.40
Sexual Dysfunction Associated With Antidepressants
Most patients with serious medical illness experience some degree of transient or chronic sexual dysfunction that can be compounded by antidepressants.
Except for buproprion, nefazodone (rarely), and mirtazapine, reports of sexual dysfunction are relatively common with antidepressant therapy. These side effects include anorgasmia, delayed orgasm, painful orgasm, reduced libido, erectile dysfunction, and penile or clitoral priapism. Patients may not spontaneously report sexual side effects, but these symptoms may lead to noncompliance with prescribed antidepressant drugs.18
Sexual dysfunction attributable to venlafaxine may be less likely than with SSRIs. In preliminary trials, venlafaxine doses at or near 375 mg/day were associated with 13% of men who reported abnormal ejaculation. But at more routine doses (near 200 mg/day), the same type of sexual dysfunction occurred in only 2% of patients. Women reported orgasmic dysfunction at a rate of about 2% when typical doses of venlafaxine were used.40 Some sexual side effects due to antidepressants may also be of therapeutic benefit. For example, the TCA clomipramine and various SSRIs (e.g., fluoxetine, sertraline) have been reported to alleviate premature ejaculation.89,90,91 Fluoxetine has been reported to restore erections and sexual potency in depressed men with impotence.18,92
A variety of largely anecdotal strategies have been used to manage SSRI-induced sexual dysfunction. These strategies have included using adjunctive agents that purportedly augment dopaminergic function (believed by some to be decreased by SSRIs and the partial cause of sexual dysfunction associated with drugs such as bupropion, amantadine, and buspirone). Dose reductions may be attempted. A short "drug holiday" prior to anticipated sexual activity is another feasible strategy when using SSRIs of shorter half-life (i.e., paroxetine, sertraline). Switching to another agent such as bupropion or possibly nefazodone may be the most effective manner for managing sexual side effects.
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DISCUSSION AND CONCLUSION
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The vast majority of patients with depression and concurrent medical illness can be safely treated with antidepressant medications by using the general guidelines we have outlined. For patients completely intolerant or resistant to antidepressants, electroconvulsive therapy may be considered, according to the guidelines for its use in medically compromised persons.1
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Jefferson J
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ABSTRACT
INTRODUCTION