Antidepressant Drugs in the Elderly

ISSN 0306-3623/98 $19.00 1 .00 PII S0306-3623(97)00070-0 All rights reserved

Gen. Pharmac. Vol. 30, No. 4, pp. 465–475, 1998 Copyright  1998 Elsevier Science Inc. Printed in the USA.

REVIEW

Antidepressant Drugs in the Elderly Pietro Gareri,1 Giuseppe Stilo,2 Ida Bevacqua,3 Rosario Mattace,3 Guido Ferreri1 and Giovambattista De Sarro1* Department of Clinical and Experimental Medicine, Chairs of Pharmacology and 3Geriatrics, Faculty of Medicine, Policlinico Materdomini via Tommaso Campanella, 2Casa di Cura ‘‘S. Vincenzo,’’ via Barlaam da Seminara 26, 88100 Catanzaro, Italy 1

ABSTRACT. 1. In this article some of the most important and tolerated drugs in the elderly are reviewed. 2. Tricyclic antidepressants have to be used carefully because of their important side effects. Nortriptyline and desipramine appear to be the best tolerated tricyclics in old people. 3. Second generation antidepressants are preferred for the elderly and those patients with heart disease as they have milder side effects and are less toxic in overdose. 4. MAO inhibitors are useful drugs in resistant forms of depression in which the above mentioned drugs have no efficacy and the last generation drugs (reversible MAO inhibitors), such as moclobemide, seem to be very successful. 5. Lithium is sometimes used especially to prevent recurrence of depression, even if its use is limited in old patients due to its side effects. 6. Psychotherapy is often used as an adjunct to pharmacotherapy, while electroconvulsant therapy is used only in the elderly patients with severe depression, high risk of suicide, or drug-resistant forms. gen pharmac 30;4:465–475, 1998.  1998 Elsevier Science Inc. KEY WORDS. Elderly, pharmacokinetics, pharmacodynamics, depression, tricyclics, atypical antidepressants, MAO inhibitors, lithium

INTRODUCTION In the recent Consensus Statement on the Diagnosis and Treatment of Depression in Late Life (NIH), it was emphasized that depression in the elderly is a persistent or recurrent disorder resulting from psychosocial stress or physiological effects of disease and can lead to disability, cognitive impairments, increased symptoms from medical illness, increased utilization of health care services, and increased rates of suicide and non-suicide mortality (Katz et al., 1994). Depression is the most common psychiatric disease in the elderly; major depression may affect 10 to 20% of hospitalized elderly, whereas 10 to 34.5% of older people in the community may have depressive symptoms if mild forms are also considered (Blazer, 1989; Murphy et al., 1988; Small, 1991; Weissman and Myers, 1978). Several biochemical changes occur in the aged brain, such as a decrease in dopamine and/or 5-hydroxytryptamine (5-HT) and/or noradrenaline (NE) and an increase in monoamine oxidase (MAO) activity. Moreover, major depression may arise from dysfunction of the limbic-hypothalamic-pituitary-adrenal axis (Friedlander et al., 1993). Elderly patients may also have concomitant physical disease, which is an additional risk factor for depression. Furthermore, the risk of suicide increases with aging and appears threefold higher in elderly men than in the general population (Chartan, 1979; Finlayson and Martin, 1982). Many of the drugs currently administered to elderly patients may induce an iatrogenic depression (Table 1).

*To whom correspondence should be addressed at: Cattedra di Farmacologia, Dipartimento di Medicina Sperimentale e Clinica, Policlinico Materdomini, via Tommaso Campanella, 88100 Catanzaro, Italy. Received 21 November 1996; accepted 24 February 1997.

However, pharmacotherapy is fundamental in this group of patients, whose age-related physiological changes, concomitant diseases, and drug treatment may alter the metabolic profile of antidepressant drugs (Greenblatt et al., 1982; Potter et al., 1991). This article reviews the changes in pharmacokinetics and pharmacodynamics occurring in old people. A literature search was made to identify articles on most of the antidepressants used in the elderly and then reviewed, in order to focus on conclusions with clinical implications. AGE-RELATED CHANGES IN PHARMACOKINETICS Age-related changes in pharmacokinetics and pharmacodynamics may cause an increase in adverse drug reactions (ADRs) in elderly people. In fact, aging causes a number of changes in drug absorption, distribution, biotransformation, and elimination (Galeotta et al., 1990). The most important factors influencing drug absorption in the aged are (a) the increase in gastric pH, because there is a reduction in acid output due to a decrease in gastric parietal cells (Greenblatt et al., 1982). The increase in gastric pH increases the absorption of basic drugs and reduces absorption of acid drugs. Since antidepressants are weakly basic, they are quickly absorbed in the first part of the small intestine, which is weakly acid (pH56.6); (b) the reduction in gastrointestinal motility, with the consequent delayed gastric emptying (Galeotta et al., 1990); (c) the reduction in splanchnic blood flow due to diminished cardiac output (Safar, 1990); (d) the decrease in absorption surface. The distribution of a drug is influenced by tissue blood flow, plasma protein binding, and the physicochemical properties of the drug itself (Galeotta et al., 1990). Moreover, it is influenced by lean

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P. Gareri et al. TABLE 1. Different types of drugs may cause depression, especially in the elderly, where polypathologies often need a polypharmacotherapy Drug type Non steroidal antiinflammatory drugs Analgesics Antihypertensive drugs Digitalis Sedative drugs Corticosteroids Antituberculotic drugs Antineoplastic drugs

Drug names Phenacetin, phenylbutazone, indomethacin Pentazocine Reserpine, thiazide diuretics, propranolol, methyldopa, guanethidine, clonidine Digoxin Benzodiazepines, barbiturates Cortisone acetate Cycloserine Vincristine, vinblastine, azathioprine, bleomycin, mithramycin

and nonlean body mass, total body water and extracellular volume; since adipose mass increases with aging, while total body water is reduced, distribution volume is less for hydrosoluble drugs and greater for liposoluble ones, such as diazepam, nitrazepam, amytriptiline, and lidocaine. Therefore these drugs tend to accumulate in adipose tissue so that their plasma half-life and their actions increase, thus causing the risk of iatrogenic effects in old people (Furlanut and Benetello, 1990; Greenblatt et al., 1982; Montamat et al., 1989). Plasma binding proteins are albumin, a1-acid glycoprotein and lipoproteins. Aging causes a reduced synthesis of these proteins; in people over 80 years old albumin synthesis is 20% less than in a young adult, and much less in the elderly subjects affected by liver and/or renal failure (Table 2). These pathological conditions may alter protein plasma levels and cause the accumulation of some substances competing with drugs in protein binding (Montamat et al., 1989). Albumin mainly binds to acid drugs, such as warfarin, salicylic acid, phenytoin, etc., whereas a1-acid glycoprotein binds to basic drugs, such as lidocaine, propranolol, and tricyclic antidepressants. Tricyclic antidepressants also bind to lipoproteins, in fact they are lipophilic (Furlanut and Benetello, 1990), therefore, any change in plasma concentration of protein binding to antidepressants might influence their distribution and concentration at receptor sites. For example binding of imipramine to lipoproteins was shown to occur in hyperlipoproteinemic patients to a greater extent than in normal people; this means that all those drugs that can influence lipoprotein plasma concentration might also influence antidepressant distribution. Regarding imipramine binding to a1-acid glycoprotein, no difference was seen among young and old adults, while the results were controversial for amitryptiline and desipramine (Wallace and Werbeeck, 1987). Another crucial point in drug kinetics is its biotransformation. Liver clearance of a drug mainly depends on liver blood flow, which decreases with aging, and on liver enzyme activity. The latter depends on phase 1 and phase 2 reactions. In phase 1 reactions the en-

zymes involved are called mixed function oxidase, composed of a number of hemoproteins, such as cytochrome-450, cytochrome b5 and a flavoprotein, NADPH-cytochrome-C reductase. Phase 2 reactions involve acetylation and conjugation reactions with glycuronic acid; while these reactions are not influenced by age, phase 1 reactions are strongly influenced by aging, sex, and genetic factors. In fact, the existence of a genetic polymorphism in the oxidative metabolism of some drugs, such as antidepressants and b-blockers has been demonstrated (Alexanderson et al., 1969; Clark, 1985; Galeotta et al., 1990); therefore, genetic mutations inherited as recessive autosomics might cause reduced synthesis of cytochrome-450. This means that for a given substance, i.e., the prototype debrisoquine, an experimental antihypertensive drug, there is fast (90% of the individuals) and slow metabolism (10%, that is, mutants) (Gonzalez et al., 1988). This is very important for tricyclic antidepressants, whose metabolism, (consisting in N-demethylation of side chain and/or hydroxylation in one of the rings of the cyclic structure by cytochrome-P450 isoenzymes) is under the control of genetic factors. Several years ago Alexanderson et al. (1969) administered the same dose of nortryptiline to monozygotic and dizygotic twins: the results were remarkable, as they showed that nortryptiline plasma concentrations were equal in monozygotics, while they were different in dizygotics. Furthermore, even in the monozygotic twins the concentrations could be different if one was simultaneously treated with other drugs. In fact, liver metabolism may also be influenced by smoking, liver diseases, alcohol, nutritional status and, especially in the elderly, concomitant administration of other drugs; this is important because drugs may increase or reduce microsomal enzyme metabolizing drugs. The former are called inductors; the latter inhibitors. Liver metabolism of a drug can also be reduced by another drug by inhibiting enzyme activity or competing with the same enzyme system. Aging also causes a reduced drug renal excretion; this even occurs

TABLE 2. Age-related pharmacokinetic changes Variables Body water (% body weight) Thin mass (% body weight) Body fat (% body weight) Seric albumin (g/dl) Kidney weight (% of young adults) Liver blood flow (% of young adults)

Young adults (20–30 years old)

Old adults (60–80 years old)

61 19 26–33 (women) 18–20 (men) 4.7 100 100

53 12 38–45 36–38 3.8 80 55–60

Antidepressants in the Elderly in the absence of overt renal failure, because glomerular filtration in old people is 30 to 35% less than young adults and tubular function and renal blood flow are also compromised (Lamy, 1986). Drugs that are excreted through glomerular filtration and are potentially toxic, e.g., digoxin, lithium, aminoglycosides, procainamide, cimetidine, and chlorpropamide. Moreover, in the elderly a normal serum creatinine does not mean a good glomerular filtration, as it can be misleading because it will be slowed in individuals with decreased muscle mass. Therefore, we need to determine creatinine clearance (CLCR) by, e.g., a formula that calculates it according to serum creatinine, age, weight, even if it is not as preferable as direct determination based on 24 hr urine collections (Beers and Ouslander, 1989; Friedman et al., 1989; Montamat et al., 1989): (1402age in years)3body weight (kg) Creatinine clearance5 723plasma creatinine AGE-RELATED CHANGES IN PHARMACODYNAMICS In the elderly some drugs may induce different pharmacological effects from those in the young for various reasons, e.g., changes in the number of receptors and binding affinity and the deficits in homeostatic mechanisms, that is, all the hormonal, biochemical, and nervous compensatory reflexes limiting the effect of a drug (Del Favero et al., 1986; Montamat et al., 1989). For example, in the elderly there may be a hortostatic hypotension following the administration of an antihypertensive drug, due to reduced autonomic functions or due to polypathologies which can alter pharmacological response. All these changes must be taken into account and we can see why, for example, old people are more sensitive to benzodiazepines, having stronger sedation even for plasma concentrations of these drugs lower than those which a young man needs for a sedative effect. In other words whatever is the therapy in an old person, we need to be careful in obtaining an efficacious pharmacological response with the lowest possible dosage. The conventional drugs used in depression are: (1) tricyclic antidepressants; (2) selective serotonin reuptake inhibitors (SSRI) and other new atypical antidepressants; (3) MAO inhibitors; (4) lithium. In this review we shall discuss those drugs which have clinical implications in the elderly, pointing out particular antidepressants that may be used with efficacy and are well tolerated. TRICYCLIC ANTIDEPRESSANTS They are formed by three benzene rings, hence tricyclic and are the most commonly used drugs in depression therapy. Their mechanisms of action consists of the inhibition of NE and 5-HT reuptake; but while biochemical block is evident on the first administration, the antidepressant effect occurs only after two or three weeks. However, chronic administration of an antidepressant shows a b-adrenergic postsynaptic receptor desensitization and a decrease in receptor density for 5-HT; this suggests that depression might be linked to receptor supersensitivity, due to the increase of receptors and their sensitivity and therefore antidepressants might act to promote receptor down-regulation (Garattini and Samanin, 1990; Sugrue, 1981). In addition, the hypothesis for the existence of specific receptors for tricyclic antidepressants is currently neither confirmed nor excluded. The classification of tricyclic antidepressants can be made on the basis of chemical structure, or of the more or less specific action on some specific receptors or of clinical effects and are shown in Tables 3, 4, and 5. In the elderly, besides major depression, tricyclic antidepressants

467 TABLE 3. The classification of antidepressants according to their chemical structure Tertiary amines

Imipramine Amitriptyline Chlorimipramine Dothiepin Trimipramine Doxepin Butriptyline Noxiptyline

Secondary amines

Desimipramine Nortriptyline Protriptyline

are very efficacious in masked depression and in pseudodementia. However, they have to be used carefully, as they may have dangerous side effects. In fact, some studies suggested they might cause arrhythmias and heart blocks (Jefferson, 1975). In addition they slow atrioventricular conduction and we can see prolonged PR, QRS, and QT intervals on the electrocardiogram, with non-specific T wave changes (Veith et al., 1982). Notwithstanding, some antidepressants, for example, imipramine, have an antiarrhythmic action, through a quinidine-like mechanism, a class Ia antiarrhythmic; but all antiarrhythmic drugs may provoke severe arrhythmias, such as ventricular fibrillation up to heart arrest, especially under anoxic conditions, ischaemic heart disease during angina and particularly myocardial infarction (Glassman and Roose, 1994). Therefore, we need to be very careful in administering a tricyclic antidepressant, especially in an old person with cardiac conduction disorders. The most frequent and important side effect of tricyclic antidepressants in an old person is orthostatic hypotension (Allen, 1987), whose mechanism is still unknown. It seems to appear even at the lowest dosages and may be related to the severity of depression, since it is less evident in normal individuals compared with depressed ones, and it is more likely to develop in depressed patients with left ventricular impairment and/or in patients taking other drugs like diuretics or vasodilators (Glassman and Preud’homme, 1993). Another remarkable point is linked to the possible habituation to this side effect after a few days of administration. However, a number of studies (Caird et al., 1973; Halaris, 1987) reported a high incidence of femoral neck fracture in over 65-year-old persons treated by tricyclics; this was caused by orthostatic hypotension. Furthermore, these drugs may have important side effects on the central nervous system (CNS), in particular, their antimuscarinic effects. The antimuscarinic effects are more marked for tertiary amines and may determine xerostomy, which may provoke moniliasis, parotitis, the rejection of dental prosthesis, and malnutrition, with dangerous hydroelectrolitic disorders. They may also provoke constipation, which at an extreme extent may cause a megacolon or a paralytic ileus and urinary retention due to the reduced action of the detrusor muscle of the bladder; therefore they are forbidden in prostatic hypertrophy and in narrow-angle glaucoma, especially when there is a concomitant cataract. Central antimuscarinic syndrome is a rare syndrome characterized by anxiety, severe confusion, delirium and coma, which requires the immediate interruption of therapy in an old person, even if its appearance is unlikely at low dosages like those used in the elderly (Jarvik et al., 1982). Recent memory deficits, the lowering of epileptogenic threshold and a ‘‘tremor-dysarthria’’ syndrome are rare side effects. Some may provoke sedation, i.e., all the compounds with an antihistaminic action, such as amitryptiline, or some difficulty in falling

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P. Gareri et al. TABLE 4. Classification of tricyclic antidepressants according to their specific action on specific receptors Reuptake inhibition of noradrenaline mainly

Imipramine Nortriptyline

Reuptake inhibition of serotonin mainly

Amitriptyline Chlorimipramine Desipramine

asleep, i.e., those drugs with a disinhibiting action, such as nortriptyline. Now, let us see in more detail some of the most popular tricyclic drugs.

Imipramine Imipramine was the first of the tricyclic antidepressants, derived from the neuropleptic chlorpromazine. It is a lipophilic, highly protein-bound drug undergoing hepatic oxidation predominantly to the pharmacologically active N-demethylation product, desipramine (von Moltke et al., 1993). Its mechanism of action consists of the inhibition of NE and 5-HT reuptake. Even though its antimuscarinic effects are less marked than other tertiary amines, such as amitryptiline, it may provoke orthostatic hypotension and therefore it has to be used with care in the elderly. Imipramine also shows a lower hepatic clearance rate in the elderly who will then have a higher steady state plasma concentration (though with considerable individual variation) than in young individuals, during long-term administration, unless dosage rates are adjusted (Abernethy et al., 1985). Therefore, some authors (Koenig, 1991) suggest that imipramine should be avoided in the elderly.

Doxepine Doxepine is a tertiary amine tricyclic with physicochemical properties similar to imipramine and amitriptyline, but with relatively low systemic availability (13 to 45%) (Ereshefsky et al., 1988). It is hepatically metabolized by demethylation to the metabolite demethyldoxepine. It mainly blocks serotonin reuptake and was recommended in affective disorders in the elderly, but it is contraindicated because of its antimuscarinic, sedative effects and some degree of orthostatic hypotension (Potter et al., 1991; Salzman, 1982).

Trimipramine It is a strongly sedative compound with severe antimuscarinic effects comparable to amitriptyline and those of doxepine. Besides, it may be used in patients with peptic ulcers, since it blocks H2 receptors (De Leo and Pavan, 1993). Secondary amines are more often used than tertiary amines in the elderly, because they have a simpler metabolism and fewer side effects, particularly desipramine, nortriptyline, maprotiline, and amoxapine.

Desipramine

Amitriptyline Amitriptyline is lipophilic like the other tricyclic antidepressants and is extensively bound; metabolism is predominantly to its pharmacologically active N-demethylate metabolite, nortriptyline. It mainly inhibits serotonin reuptake. Once it was used in the elderly for its sedative effects, but it is not now the main drug used in old people, since it has severe antimuscarinic and hypotensive effects (De Leo and Pavan, 1993). Furthermore, it has been frequently associated with central anticholinergic syndromes and conduction disturbances; therefore it has to be administered at low dosages. A clear effect of age on the pharmacokinetics of amitriptyline is not well established; some studies suggest an increase in t1/2 with age, a decreased clearance and a resulting increased steady state serum concentration (Css), and especially an interindividual variation (von Moltke et al., 1993). Some reviewers feel that this drug has no place in the treatment of depression in the elderly (Koenig, 1991), given the potentially severe adverse effects.

Desipramine is lipophilic and highly tissue and protein bound; its major metabolic pathway is via hepatic aromatic 2-hydroxylation to 2-hydroxydesipramine, a metabolite which probably has both therapeutic and toxic activity and is excreted intact by the kidneys (Potter et al., 1979). It blocks NE reuptake, causes mild side effects if compared to imipramine or amitriptyline and so appears as a potential choice in vulnerable populations such as old people, but its disinhibiting effects may cause insomnia. Some findings suggested that clearance of desipramine via hydroxylation is less sensitive to age than is clearance of imipramine by demethylation, when evaluated in the same cohort of young and elderly volunteers (Abernethy et al., 1985). Besides, patients with decreased renal function secondary to age or disease might have impaired excretion of the 2-hydroxymetabolite, but whether this may have clinical implications for therapeutic or toxic effects is not yet established.

Nortriptyline TABLE 5. Classification of tricyclic antidepressants according to their clinical effects Sedative-antianxiety action

Amitriptyline Chlorimipramine Trimipramine

Disinibition action

Imipramine Desimipramine Nortriptyline

Like its parent drug amitriptyline, nortriptyline is a lipophilic and protein-bound compound. Metabolism is primarily by hepatic oxidation to 10-hydroxy-nortriptyline, which may contribute to therapeutic and toxic effects. This metabolite is excreted intact by the kidneys. It is the most studied of the tricyclics (Rubin et al., 1985), especially with regard to use in the elderly. Its mechanism of action consists of the inhibition of noradrenaline and serotonin reuptake and it is less sedative and antimuscarinic than tertiary amines. It has mild hypotensive effects; the therapeutic window, which is lower in the elderly than in the young, is between 50–140 ng/ml. Moreover,

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TABLE 6. Mean dosages, plasma half-life and side effects of some tricyclics in the elderly Drug Imipramine Desipramine Chlorimipramine Trimipramine Amitriptyline Nortriptyline Doxepin

Side effects

Mean dosage/day (mg/die)

Plasma half-life (hours)

Sedation

Hypotension

Cardiac

Antimuscarinic

Seizures

30–100 30–125 30–100 75–150 30–100 25–75 75–150

10–25 12–24 17–28 9–25 10–22 20–50 12–23

1 1 1 1 111 1 11

11 11 11 11 11 1 11

11 11 11 11 111 1 11

11 11 11 11 111 11 111

1 1 1 1 1 1 1

Note that nortriptyline appears to be one of the best tolerated tricyclics in old people.

its clearance seems markedly lower only in elderly patients with concurrent medical illness (Dawling et al., 1980; von Moltke et al., 1993); metabolite concentrations seem to be higher in the elderly, probably due to a decrease in renal clearance. However, the link between concentration and any clinical effect remains uncertain.

It is a tetracyclic, even though it is classified among secondary amines, with fewer side effects than nortriptyline. It is used largely in the elderly population, but high dosages must be avoided due to the possible appearances of seizures (Salzman, 1993).

zodone appears to confer little advantage over other available antidepressants, such as amitriptyline, imipramine, fluoxetine, and mianserin; it may be a drug of first choice in elderly patients in whom anxiety and insomnia are problems and in those patients who are unresponsive to or cannot tolerate therapy with other agents (Haria et al., 1994). Available data suggest that trazodone clearance may be impaired in the elderly, particularly in elderly men (Nemeroff, 1994). A need for reduced dosage can be anticipated for the elderly, although a relationship between steady state serum concentration (Css) and clinical effects is not established. Studies are also required to establish its place in long term prophylactic therapy for recurrent depression.

Amoxapine

Fluoxetine

It is derived from the neuroleptic loxapine, but is not used in the elderly because of its possible impairment of dopaminergic neurotransmission which causes extrapyramidal symptoms (De Leo and Pavan, 1993). Table 6 summarizes the main characteristics of these drugs, including mean dosage and side effects.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI), it has a bicyclic structure, it is protein-bound and undergoes hepatic biotransformation to metabolites that include the N-demethylation product norfluoxetine, pharmacologically active. Both parent drugs are characterized by long t1/2 values (1 to 3 days for fluoxetine and 7 to 15 days for norfluoxetine) and therefore fluoxetine is administered once daily; its clinical effects are very slow, but it is as effective as tricyclic antidepressants, even though it is structurally unrelated and is one of the first-line drugs in the elderly. Because fluoxetine is a relatively new antidepressant, few data on its pharmacokinetics in the elderly are available. Limited information suggests minimal age-related pharmacokinetic changes (Harris and Benfield, 1995; von Moltke et al., 1993). Moreover, it is associated with fewer antimuscarinic, cardiovascular and CNS adverse events, but greater numbers of gastrointestinal adverse events than those reported for the tricyclic antidepressants (Harris and Benfield, 1995). It often causes insomnia, nausea, and vomiting. High serum concentrations of fluoxetine were described to probably cause widespread cognitive disorders, such as hyperkinetic delirium (Leinonen et al., 1993), but this needs to be confirmed. One should be careful when prescribing fluoxetine in the elderly, notably when a diuretic is also prescribed, because severe hyponatremia, possibly due to inappropriate antidiuretic hormone secretion, was shown in 14 cases in literature (TenHolt et al., 1994).

Maprotiline

ATYPICAL ANTIDEPRESSANTS Recently, apart from tricyclic antidepressants, new molecules with the effects of tricyclics, but with far fewer side effects have been produced. Among these, trazodone, fluoxetine, fluvoxamine, paroxetine, tianeptine, nefazodone, sertraline, minaprine, which are serotonin reuptake inhibitors, venlafaxine, which blocks serotonin and noradrenaline reuptake, dothiepin and viloxazin, which block noradrenaline reuptake, amyneptine, sulpiride, which block dopamine reuptake, lofepramine, mianserin, S-adenosyl-methionine, alprazolam and l-tryptophan, which have different mechanisms of action.

Trazodone Trazodone has a different chemical structure from the other antidepressants; in fact it is a triazolopyridine derivative biotransformed principally to the active metabolite metachlorophenylpiperazine (mCPP) by hepatic microsomal oxidation. It causes an increased NE release and turnover, by acting on a2-presynaptic receptors and has an efficacious antidepressant action in old people and a moderate anxiolytic and hypnotic activity (Haria et al., 1994). The most common side effects are dizziness, drowsiness, and especially orthostatic hypotension, while there are no antimuscarinic effects, apart from xerostomy. Priapism, heart arrhythmias were also observed in a few cases; in addition, since it may cause gastric irritation its administration after meals is appropriate. In terms of therapeutic efficacy, tra-

Fluvoxamine Fluvoxamine is well absorbed following oral administration to healthy volunteers; mean elimination half-life is approximately 19 and 22 hours after single and multiple doses, respectively, and is not significantly increased in the elderly. It undergoes extensive hepatic metabolism to at least 11 metabolites of which none possesses psychotropic activity. More than 90% of a dose is eliminated in the

470 urine as metabolites, while 4% of a dose is eliminated in the urine as unchanged drug (Wilde et al., 1993). It facilitates 5-HT neurotransmission via potent and selective inhibition of serotonin reuptake into presynaptic neurons. Its efficacy appears to be comparable to that of imipramine, clomipramine, dothiepin, desipramine, amitriptyline, lofepramine, maprotiline, mianserin, and moclobemide (Wilde et al., 1993). It is very similar to fluoxetine, including the once daily administration and has mild side effects, i.e., nausea and vomiting. It seems to be particularly beneficial in potentially suicidal patients with severe depression, in those with an underlying compulsive personality or with cardiovascular disorders, in patients with coexisting anxiety or agitation, and in the elderly (Wilde et al., 1993). In fact in a 6-week comparative, nonblind general practice study of more than 5,600 patients with depression, the efficacy of fluvoxamine in patients aged 60 years or older (n51096) was similar to that in younger patients (Martin et al., 1987). In another large noncomparative study of patients with depression, the efficacy of fluvoxamine was also similar in elderly and younger patients (Stollmaier et al., 1989).

Paroxetine This phenyl-piperidinic derivative has been introduced recently, and has a strong and selective serotonin reuptake inhibition. It has also little affinity for a-adrenergic, dopamine, histamine, and acetylcholine receptors (Nemeroff, 1993). Its bioavailability is not affected by food or antiacids and its mean plasma half-life of about 24 hours is consistent with once a day dosing. It undergoes a partially saturated first pass metabolism and in the plasma 95% is bound to proteins; it is eliminated after transformation in the liver into pharmacologically inactive metabolites (Hiemke, 1994). Its high affinity to the cytochrome-P450, isoenzyme CYP2D6, indicates that interference occurs with other drugs metabolized via the same isoenzyme. Paroxetine causes a marked decrease of anxiety, improves the quality of sleep in depressed patients, and does not alter psychomotor performances. It demonstrated comparable efficacy to fluoxetine in the treatment of elderly depressed patients, improving all measures of cognitive and behavioral function (Geretsegger et al., 1994). Paroxetine has been shown to be efficacious in preventing the relapse of depression during long-term treatment, even if further research is required and has few side effects, such as nausea and other gastrointestinal disturbances, few antimuscarinic and CNS adverse effects, which rarely leads to dose reduction or drug discontinuation (Holliday and Plosker, 1993). It should not be coadministered with MAO inhibitors or with l-tryptophan.

P. Gareri et al. (Wilde and Benfield, 1995). Therefore, it is particularly suitable in the elderly.

Nefazodone It is a new serotoninergic antidepressant, with an efficacy in elderly patients comparable to imipramine. A few side effects have been reported, such as dose-related impairment of cognitive and memory functions. However, its action still needs to be better investigated (Van Laar et al., 1995).

Sertraline Sertraline is a 5-HT reuptake inhibitor that has been approved for use in the treatment of depression; its side effects profile is similar to that of fluoxetine. It is nonsedating, free of cardiac effects, does not cause orthostatic hypotension, urine retention, or blurred vision. The only side effects involve the gastrointestinal tract. This makes sertraline a safe drug in depressed elderly patients (Auster, 1993). Another selective inhibitor of the transport of 5-HT into nerve terminals and other cells that accumulate this neurotransmitter is citalopram (Luo and Richardson, 1993). It is also effective therapeutically as the well established antidepressants, but causes considerably fewer side effects than amitriptyline. Citalopram appears to have minimal effects on the cardiovascular system and is one of the few antidepressants to be eliminated by the kidneys. It is also recommended in elderly depressed patients. A 5-HT reuptake inhibitory antidepressant recently tested in elderly volunteers is medifoxamine (Gainsborough et al., 1994), but the promising results require further confirmation.

Minaprine It has an original chemical structure and not only increases intracerebral levels of serotonin but also activates dopaminergic neurotransmission. Minaprine appears to have the same efficacy as imipramine, but with fewer side effects. The only side effects are insomnia and restlessness and is devoid of cardiovascular side effects, therefore it is commonly used in the elderly (DeLeo and Pavan, 1993; Salzman, 1993).

Dothiepin Its use in the elderly is controversial, because of the frequent side effects, such as tachycardia and orthostatic hypotension (Bressler and Katz, 1993; De Leo and Pavan, 1993).

Tianeptine Tianeptine is a new antidepressant agent, both structurally, as it is a modified tricyclic and in terms of its pharmacodynamic profile. It stimulates the uptake of 5-hydroxytryptamine in rat brain synaptosomes and rat and human platelets, increases 5-hydroxyindoloacetic acid (5-HIAA) levels in cerebral tissue and plasma and reduces serotoninergic-induced behavior (Wilde and Benfield, 1995). Its efficacy in major depression, depressed bipolar disorder with or without melancholia or dystymic disorder, in depression and coexisting anxiety appears to be similar to that of amitriptyline, imipramine, and fluoxetine and even superior to that of maprotiline. It is also very effective in the treatment of depression in elderly and post-alcohol– withdrawal patients and in reducing the rate of recurrence. Tianeptine is well tolerated in short and long term therapy; dry mouth, constipation, dizziness, drowsiness, and postural hypotension are less frequent with tianeptine than with tricyclics, such as amitriptyline

Venlafaxine Venlafaxine is a new antidepressant that inhibits the reuptake of 5-HT and NE, with a weak reuptake inhibition of dopamine. The monoaminergic uptake inhibition is similar to that of the older tricyclic antidepressants, with the advantage of the lack of adverse drug effects associated with activity at other receptors (Bolden-Watson and Richelson, 1993), especially in the long-term treatment of depression (Shrivastava et al., 1994) and has an enhanced response with increasing doses (Rudolph et al., 1991). In a randomized, double-blind fixed-dose comparison of placebo and three doses of venlafaxine (75, 225, and 375 mg), the drug was more effective than placebo in relieving the symptoms of depressed outpatients (Schweitzer et al., 1991). In other studies it showed an activity at least comparable to clomipramine and imipramine in the treatment of major depression and unipolar depression, respectively (Samuelian et al.,

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1992; Schweitzer et al., 1994), and superior to fluoxetine (Clerc et al., 1994). The most commonly reported adverse drug effects associated with venlafaxine were nausea, somnolence, and dizziness. Pulse rates and blood pressure increased slightly, while weight decreased.

Viloxazine It has a bicyclic structure and potentiates noradrenergic neurotransmission. Viloxazine has no cardiovascular and anticholinergic effects. Headache and nausea (of central origin) are the main side effects (Bressler and Katz, 1993; De Leo and Pavan, 1993).

Amineptine It is a tricyclic compound, even though it differs by the presence of a long chain that ends with an acid radical. Its psychostimulant effect is only inferior to MAO inhibitors. Anxiety was observed in the first two weeks of treatment and rarely, cholestatic hepatitis (Voltz and Moller, 1994).

Sulpiride This recently introduced drug belongs to the benzamides, therefore it is practically a neuroleptic, mainly used in dysthymia. In the elderly it may cause sedation and hypotension, together with a number of side effects that are characteristic of this class of drugs, i.e., precocious dyskinesia (stiff neck, oculogir crises, trismus), extrapyramidal syndrome, requiring an antiparkinsonian treatment, tardy dyskinesia, observed in the case of prolonged treatments and some endocrine effects, such as hyperprolactinemia, galactorrhea, gynecomastia, etc. It may also potentiate the effects of antihypertensive, hypnotic, and analgesic drugs (Bressler and Katz, 1993; Nair et al., 1995).

Mianserin It is a tetracyclic compound that seems to have only a mild effect on the reuptake of monoamines; it increases intrasynaptic adrenaline by blocking the receptors that control the release of noradrenaline through a negative feedback. It is recommended for the treatment of depressive illness associated with anxiety and agitation, including severe forms of depression, in the elderly and in those patients with a suicidal tendency (Demling, 1993). Moreover, there seem to be no clinically important changes in the pharmacokinetics of this drug with advancing age (Leinonen et al., 1994), so that it can be regarded as an antidepressant with relatively few side effects in the elderly. Mianserin causes marked sedation, mild orthostatic hypotension, and has no antimuscarinic effects.

Alprazolam Although a benzodiazepine, alprazolam has been shown to be a good and safe antidepressant drug, especially in those forms of depression associated with anxiety. It may be administered to elderly patients, even though in mild dosages; it is not to be used if a narrow-angle glaucoma is present (De Leo and Pavan, 1993).

S-adenosyl-methionine (SAMe) It may be used in the elderly because it has practically no side effects. SAMe increases noradrenaline and serotonin turnover, stimulates phospholipid methylation, and so membrane synaptosome fluidity is preserved (Salzman, 1993). L-tryptophan

It is a serotonin precursor and can potentiate tricyclic and MAO inhibitors’ antidepressant action (De Leo and Pavan, 1993). Table 7 summarizes the main characteristics of these drugs, including mean dosage and side effects.

Lofepramine It differs from imipramine being lipophilic, but has fewer side effects, though its safety in the elderly has not been investigated. In fact, recent case reports of hepatic toxicity caused clinicians to question its use in patients who frequently have concomitant physical illness. However, for the overwhelming majority of patients, any rise of liver enzyme activity seems to be transient (Kelly et al., 1993), even if liver function monitoring for the first 12 weeks of treatment is recommended.

MAO INHIBITORS Drugs of this class inhibit mitochondrial monoamine oxidase (MAO) both in the CNS and in peripheral tissues. MAO are enzymes of two classes (isoenzymes), A and B: the former mainly metabolize NE (Fig. 1) and 5-HT (Fig. 2), while the latter metabolize dopamine. However, MAO-B inhibitors, like l-deprenyl, even though they have less side effects, are not as potent as MAO-A inhibitors in antidepressant action. The antidepressant efficacy of

TABLE 7. Mean dosages, plasma half-life and side effects of some atypical antidepressants in the elderly Drug Trazodone Fluoxetine Fluvoxamine Paroxetine Minaprine Viloxazine Venlafaxine Amineptine Sulpiride Mianserin

Side effects

Mean dosage/day (mg/die)

Plasma half-life (hours)

Sedation

Hypotension

Cardiac

Antimuscarinic

Seizures

75–300 20–40 100–200 20 150–200 150–300 75–375 100–200 25–50 40–80

6–8 48–68 15–20 24 2–20 2–6 10–12 24–48 15–30 6–30

11 2 2 2 2 1 11 2 1 11

1 2 2 2 1 2 2 2 1 1

2 2 2 2 2 2 2 2 2 2

1 2 2 2 2 1 2 1 1 2

2 2 2 2 2 2 12 2 2 2

Note that these drugs are far better tolerated than tricyclics, even if they are mostly proven to be very efficacious, so that they are the first choice antidepressants in the elderly.

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P. Gareri et al.

FIGURE 1. MAO-A metabolizes noradrenaline into an aldehyde, from which derive dihydroxymandelic acid (DHMA) and dihydroxyphenylglycol (DHPG). Catechol-O-methyltransferase (COMT) metabolizes these compounds into vanil-mandelic acid (VMA) and methoxyhydroxyphenylglycol (MHPG), respectively.

MAO-A may be due to the increase in the intrasynaptic concentration of monoamines; nevertheless, as seen with tricyclics, while enzymatic block is evident after the first administration, the clinical results need 15–20 days to appear. Therefore, it is currently thought that enzymatic block is only the first step of a more complex mechanism (Hauger et al., 1988). MAOIs are recommended in forms of depression refractory to TCAs, in panic attack disturbances, in dementia-associated depression (nonsevere forms), in atypical depression (West and Dally, 1959) and in social phobia (Fyer and Gorman, 1986). They have mild antimuscarinic effects; it is very unusual for a patient treated with this drug to complain of xerostomy, sweating, accommodation disturbances, or reduction in sexual potency. Nevertheless, they may provoke orthostatic hypotension, insomnia, tremors, mental tension and especially severe hypertensive crises, which may potentially lead to death. This can occur following ingestion of food containing tyramine, tryptophan, and tyrosine, such as cheese, alcohol (in particular red wine), seasoned food, bananas, beans, dried fruit, pineapple, acid creams, etc. (‘‘cheese effect’’). In fact, tyramine present in food is usually metabolized by intestinal and hepatic MAO. If they are inhibited by an MAOI, tyramine passes into the bloodstream and may cause hypertensive crises. However, this may occur only with the older MAOIs, characterized by an irreversible link to MAO, such as phenelzine, isocarboxazide, tranylcipromine (Table 8). This means that they are not suitable in elderly patients. Nevertheless, recent research resulted in the development of selective and reversible monoamine oxidase inhibitors of isoenzyme A (RIMAs) (Nair et al., 1995). They have an antidepressant activity comparable to TCAs and new antidepressants but have fewer side effects than TCAs and classical MAOIs. They include moclobemide, broforamine, toloxatone, and cimoxatone, of which moclobemide is the most studied and is used in the treatment of depression in elderly people. Moclobemide is a derivative of benzamide that inhibits MAO-A rapidly, selectively, and reversibly. Recovery of MAO-A activity occurs within 16 hours (Kan and Strolin Benedetti, 1980). This new MAOI causes a moderate increase of noradrenaline, dopamine, and especially serotonin in the rat central nervous system. Moclobemide is rapidly and almost completely absorbed from the gastrointestinal tract and undergoes extensive first pass hepatic metabolism. About 50% is bound to proteins; its clearance is almost exclusively due to hepatic metabolism and its metabolites may have no or only modest activity. The parent compound has a short elimination half-life of 1–2 hours, which is lower than with other RIMAs (Amrein et al., 1989; Guentert et al., 1990), while it is prolonged in patients with hepatic dysfunctions (Stoeckel et al., 1990). Furthermore some studies suggest there is no significant difference in absorption and disposition of moclobemide be-

tween elderly people and young healthy volunteers and depressed patients (Maguire et al., 1991). Except for cimetidine, moclobemide does not appear to interact with several classes of drugs commonly used in elderly patients, such as antihypertensive agents, benzodiazepines, hypoglycemics, and anticoagulants (Zimmer et al., 1990). At therapeutic doses, moclobemide produced minimal potentiation of the pressor response to intravenous tyramine or phenylephrine; potentiation was lower when tyramine was taken with food, therefore it is recommended that it is given postprandially (Korn et al., 1988). The neuroendocrine effects of this drug in humans are minimal, that is, a dose-related and transient hyperprolactinemia, a rise in plasma testosterone level and an increase in melatonin synthesis in pineal gland (Markianos et al., 1991; Oxenkrug et al., 1985; Scheinin et al., 1990). In depressed patients, moclobemide caused progressive improvement in sleep continuity with increased stage II non-REM and REM sleep (Monti et al., 1990). An important point is that both elderly volunteers and depressed patients showed an improvement of cognitive functions after the administration of moclobemide (Postma and Vranesic,1983; Wesnes et al., 1989). A mild impairment, however, was noticed in elderly volunteers on psychomotor function, but not in automobile-driving performance (Ramaekers et al., 1992). In elderly patients this drug is used at a dosage of 300–600 mg daily; it was administered either twice or three times daily, with a usual maintenance dose of 300–600 mg daily; doses are administered twice or three times daily and the treatment duration varies between 4 and 8 weeks. It has an antidepressant efficacy comparable to tricyclic antidepressants and newer generation antidepressants; however, further studies are needed to confirm these promising results. LITHIUM Lithium is used in short-and long-term treatment of bipolar illness, in mania, as well as in some patients with tricyclic antidepressant resistant or recurrent unipolar depression (Flint and Rifat, 1994). It

FIGURE 2. MAO-A metabolizes 5-hydroxytryptamine into 5-hydroxyindolacetic acid (5-HIAA).

Antidepressants in the Elderly

473

TABLE 8. Pharmaceutical preparations and mean dosage of earlier MAOI Pharmaceutical preparations Phenelzine Isocarboxazide Tranylcipromine Tranylcipromine 1 Trifluperazine

Mean dosage (mg/day)

Tablets 15 mg Tablets 10 mg Tablets 10 mg

15–30 10–30 20–30

Sugar-coated tablets

10–30

is administered as the carbonate or citrate salt, undergoes no metabolism and is excreted by the kidneys. It has a stabilization effect on neurotransmission and on receptor systems. Given its low therapeutic index, plasma concentration monitoring is essential (Salzman, 1982) and as suggested by some studies (Abou-Saleh and Copen, 1993) adequate efficacy in elderly patients can be achieved at relatively low plasma concentrations (0.5–2 mEq/l), even though it is hydrosoluble and the volume of distribution for hydrosoluble drugs is decreased in old individuals. On the other hand, as the therapeutic range for lithium in the elderly becomes reduced with age, the renal function declines with age, a reduction in its dosage is needed in old people (Hewick et al., 1977). Moreover, the elderly may have concomitant physical disease which needs the administration of different medications that can disrupt water and electrolytes balance and lead to potentially hazardous fluctuations in lithium concentrations (DeAngelis, 1990). Moreover, lithium can interfere with renal sodium excretion, can alter thyroid function and heart conduction disturbances. Rare side effects are nausea, diarrhea, abdominal pain, and weakness. The concomitant administration of a thiazide diuretic should be avoided or at least followed by a decrease in lithium dosage, as its excretion might be reduced. ELECTROCONVULSIVE THERAPY Electroconvulsive therapy may be used in those patients where pharmacological therapy is not effective and/or have a high risk of suicide. The most common side effect is a transient loss of memory, which might be avoided through the stimulation of the nondominant hemisphere. Moreover the increased intracranial pressure might provoke the herniation of brian tissue through the tentorium. Subjects with osteoporosis may undergo fractures from convulsive movements. Finally, psychotherapy remains an indispensable help to pharmacological treatment. CONCLUSIONS Depression is a common but treatable condition in the elderly, which is often hard to diagnose, as it may be masked by hypochondriasis or somatization. Special problems in diagnosis may also arise from bipolar disorder, pseudodementia, pathological grief and organic mood disorder as those are related to medications or physical illness (Casey, 1994). The difficulties in diagnosing depression may lead to unnecessary investigations, delay in treatment and an increased risk of suicide, especially in men. Age-related changes in pharmacokinetics and in pharmacodynamics have to be kept in mind before prescribing an antidepressant therapy in an elderly patient. Furthermore, the main aim of a pharmacological treatment for depression is not only to resolve the acute episode, but also to prevent relapse and to enhance the quality of life in an old individual once that full remission is achieved (Cassano et al., 1993). Tricyclic antidepressants are the first line drugs in young people, whereas in the elderly they have to be used carefully due to their important side effects. Nortriptyline and desipramine appear to be the best tolerated tricyclics in old people. However, second generation antide-

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