Conventional and new antidepressant drugs in the elderly

Progress in Neurobiology 61 (2000) 353±396

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Conventional and new antidepressant drugs in the elderly Pietro Gareri, Umberto Falconi, Pasquale De Fazio, Giovambattista De Sarro* Chair of Pharmacology and Chair of Psychiatry, Department of Clinical and Experimental Medicine ``Gaetano Salvatore'', Faculty of Medicine, University of Catanzaro, Policlinico Materdomini, via Tommaso Campanella, 88100 Catanzaro, Italy Received 6 August 1999

Abstract Depression in the elderly is nowadays a predominant health care problem, mainly due to the progressive aging of the population. It results from psychosocial stress, polypathology, as well as some biochemical changes which occur in the aged brain and can lead to cognitive impairments, increased symptoms from medical illness, higher utilization of health care services and increased rates of suicide and nonsuicide mortality. Therefore, it is very important to make an early diagnosis and a suitable pharmacological treatment, not only for resolving the acute episode, but also for preventing relapse and enhancing the quality of life. Age-related changes in pharmacokinetics and in pharmacodynamics have to be kept into account before prescribing an antidepressant therapy in an old patient. In this paper some of the most important and tolerated drugs in the elderly are reviewed. Tricyclic antidepressants have to be used carefully for their important side e€ects. Nortriptyline, amytriptiline, clomipramine and desipramine as well, seem to be the best tolerated tricyclics in old people. Second generation antidepressants are preferred for the elderly and those patients with heart disease as they have milder side e€ects and are less toxic in overdose and include the so called atypicals, such as selective serotonin reuptake inhibitors, serotonin noradrenalene reuptake inhibitors and noradrenaline reuptake inhibitors. Monoamine oxidase (MAO) inhibitors are useful drugs in resistant forms of depression in which the above mentioned drugs have no ecacy; the last generation drugs (reversible MAO inhibitors), such as meclobemide, seem to be very successful. Mood stabilizing drugs are widely used for preventing recurrences of depression and for preventing and treating bipolar illness. They include lithium, which is sometimes used especially to prevent recurrence of depression, even if its use is limited in old patients for its side e€ects, the anticonvulsants carbamazepine and valproic acid. Putative last generation mood stabilizing drugs include the dihydropyridine L-type calcium channel blockers and the anticonvulsants phenytoin, lamotrigine, gabapentin and topiramate, which have unique mechanisms of action and also merit further systematic study. 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. # 2000 Published by Elsevier Science Ltd. All rights reserved. Keywords: Elderly; Pharmacokinetics; Pharmacodynamics; Depression; Tricyclics; Atypical antidepressants; MAO inhibitors; Lithium

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355

2.

Incidence and prevalence of depression in the elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355

3.

Symptomatology and aetiology of depression in the elderly. . . . . . . . . . . . . . . . . . . . . . . . . 357

4.

Age-related changes in pharmacokinetics and pharmacodynamics . . . . . . . . . . . . . . . . . . . . 359 4.1. Age-related changes in pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 4.1.1. Genetic polimorphism of hepatic enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . 360

* Corresponding author. E-mail address: [email protected] (G. De Sarro). 0301-0082/00/$ - see front matter # 2000 Published by Elsevier Science Ltd. All rights reserved. PII: S 0 3 0 1 - 0 0 8 2 ( 9 9 ) 0 0 0 5 0 - 7

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4.2.

Age-related changes in pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362

5.

Mechanism of action of antidepressants 5.1. 5-HT receptors . . . . . . . . . . . . . 5.2. Adrenoreceptors . . . . . . . . . . . . 5.2.1. a-Adrenoceptors . . . . . . 5.2.2. b-adrenoceptors . . . . . . 5.3. Dopamine receptors. . . . . . . . . . 5.3.1. D1-like receptors . . . . . . 5.3.2. D2-like receptors . . . . . . 5.4. g-aminobutyric acid . . . . . . . . . .

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362 365 367 367 367 368 371 371 371

6.

Antidepressant drugs in the elderly . . . . . . . . 6.1. Tricyclic antidepressants . . . . . . . . . . 6.1.1. Imipramine. . . . . . . . . . . . . . 6.1.2. Clomipramine . . . . . . . . . . . . 6.1.3. Amitriptyline . . . . . . . . . . . . 6.1.4. Doxepine . . . . . . . . . . . . . . . 6.1.5. Trimipramine . . . . . . . . . . . . 6.1.6. Desipramine . . . . . . . . . . . . . 6.1.7. Nortriptyline. . . . . . . . . . . . . 6.1.8. Dothiepin . . . . . . . . . . . . . . . 6.1.9. Maprotiline . . . . . . . . . . . . . 6.1.10. Amoxapine . . . . . . . . . . . . . . 6.2. Atypical antidepressants. . . . . . . . . . . 6.2.1. Fluoxetine . . . . . . . . . . . . . . 6.2.2. Fluvoxamine. . . . . . . . . . . . . 6.2.3. Paroxetine . . . . . . . . . . . . . . 6.2.4. Sertraline . . . . . . . . . . . . . . . 6.2.5. Citalopram . . . . . . . . . . . . . . 6.2.6. Tianeptine . . . . . . . . . . . . . . 6.2.7. Nefazodone . . . . . . . . . . . . . 6.2.8. Trazodone . . . . . . . . . . . . . . 6.2.9. Minaprine . . . . . . . . . . . . . . 6.2.10. Venlafaxine. . . . . . . . . . . . . . 6.2.11. Viloxazine . . . . . . . . . . . . . . 6.2.12. Amineptine. . . . . . . . . . . . . . 6.2.13. Nomifensine . . . . . . . . . . . . . 6.2.14. Sulpiride and amisulpride . . . 6.2.15. Lofepramine . . . . . . . . . . . . . 6.2.16. Mianserin . . . . . . . . . . . . . . . 6.2.17. Alprazolam. . . . . . . . . . . . . . 6.2.18. Reboxetine . . . . . . . . . . . . . . 6.2.19. S-adenosyl-methionine (SAM) 6.2.20. L-tryptophan . . . . . . . . . . . . 6.2.21. Mirtazapine . . . . . . . . . . . . . 6.2.22. Hypericum . . . . . . . . . . . . . . 6.2.23. Bupropion . . . . . . . . . . . . . . 6.3. Mao-inhibitors . . . . . . . . . . . . . . . . . 6.3.1. RIMAs . . . . . . . . . . . . . . . . 6.4. Mood stabilizing drugs . . . . . . . . . . . 6.4.1. Lithium . . . . . . . . . . . . . . . . 6.4.2. Carbamazepine . . . . . . . . . . . 6.4.3. Phenytoin . . . . . . . . . . . . . . . 6.4.4. Valproic acid . . . . . . . . . . . . 6.4.5. Verapamil. . . . . . . . . . . . . . . 6.4.6. Lamotrigine . . . . . . . . . . . . . 6.4.7. Gabapentin. . . . . . . . . . . . . . 6.5. Other antidepressant agents . . . . . . . .

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7.

Electroconvulsive therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

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8.

355

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388

1. Introduction Depression in the elderly is nowadays a predominant health care problem, mainly due to the progressive aging of the population. In fact, the statistics of the United Nations and the World Bank pointed out that by the year 2010 approximately 7.3% of the world's population will be over the age of 65 and by the year 2030 a further increase up to 20% is foreseen (Mendlewicz, 1998). Depression is the most common psychiatric disease in the elderly; major depression may a€ect from 10 to 20% of hospitalized elderly, while from 10 to 34.5% of older persons in the community may have depressive symptoms if mild forms are considered too (Blazer, 1989; Murphy et al., 1988; Small, 1991; Weissman et al., 1988; Linden et al., 1988). In the Consensus Statement on the Diagnosis and Treatment of Depression in Late Life (National Institute of Health), it was emphasized that depression in the elderly is a persistent or recurrent disorder resulting from psychosocial stress or physiologic e€ects 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 nonsuicide mortality (Katz et al., 1994). Data from Diagnostic and Statistical Manual for Mental Disorders, 4th edition (DSM-IV) have shown that major depressive disorder is more frequent in young people, whilst dysthymia and depressive disorder not otherwise speci®ed prevail among the elderly (Gottfries, 1998). These results don't mean that depression is less severe in elderly people than in younger, since high suicide rates have been especially found in the former. Moreover, depression is dicult to diagnose in elderly people; depressive symptoms are often masked by somatic complaints or by cognitive symptoms, conditions once called `masqued depression' or `pseudodemence'. Therefore, depression in the elderly is often under-recognized and under-treated (Lecrubier, 1998); this may be due to the mistake, both from the physician and from the patient, of considering depression as a physiologic response to aging. Other factors may be the lack of consciousness of disease from the

patient, the presence of concomitant diseases, especially dementia (Bayer and Pathy, 1989) and the usully atypical onset of depression in elderly people (Blazer, 1980). The increased incidence and prevalence of depression with aging can be also explained considering some stressors which elderly people frequently have to face, such as physical disability, bereavement, loss of prestiges, cognitive abilities and social isolation (Koenig and Blazer, 1992). In fact, it was shown that the nature and quality of social support, de®ned by the number of relationships with friends and relatives is one of the major risk factors for depression in the elderly (Krause et al., 1989; Russel and Cutrona, 1991; Owmank et al., 1992). Female sex, widowhood and single life are risk factors for depression too (Dufouil et al., 1995; Blazer et al., 1991; Okwumabua et al., 1997). Interestingly, some studies have shown that aging itself is not a risk factor for depression (Blazer et al., 1991; Roberts et al., 1997). Moreover, major depression may arise from disfunction of the limbic-hypothalamic-pituitary-adrenal axis (Friedlander et al., 1993). Depression may also be caused by a various number of drugs currently administered (see below); this is remarkable especially in elderly people, where polypathology is often associated to polypharmacotherapy. Depression has also global consequences on quality of life and social functioning, leading to distress, loss of role and grati®cation, narrowing of the social repertoire and shortening of life span (Warner, 1998). In fact, mortality may also be higher in the elderly depressed compared with controls (Murphy, 1983); the excess mortality was accounted for by a variety of diseases, such as vascular and respiratory diseases and cancer.

2. Incidence and prevalence of depression in the elderly Epidemiologic studies of depression in the elderly raise a number of methodological problems, because of various reasons, such as the lack of a clear de®nition of elderly, the di€erent populations studied (i.e. general population, patients in primary care units, instituzionalized patients, etc.), the methods of assessment used (self-rating scales, short or structured interviews, diagnostic criteria check lists) (Lepine and

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Bouchez, 1998). Among the methods of assessment the Zung Self Rating Scale (Zung, 1965) and the Center for Epidemiologic Studies Depression Scale (CES-D) (Radlo€, 1977) are the non speci®c self-rating scales most frequently used in epidemiological studies of depression in the elderly, but they have a low clinical sensitivity. The Geriatric Depression Scale (GDS) (Yesavage et al., 1983) is the most frequently used and speci®c scale in the elderly and has the only limit that it cannot be used in subjects with severe cognitive impairment. A number of United States epidemiological studies have reported prevalence rates of depressive symptoms in the community about 15%. The assessment scale most frequently used in these studies was the CES-D (Blazer et al., 1991; Potter et al., 1995; Okwumabua et al., 1997) (Table 1). European studies have also shown a similar prevalence rate (Livingston et al., 1990; Dufouil et al., 1995; Prince et al., 1997; Kirby et al., 1997) (Table 1). In an elderly population in Finland, the estimated prevalence of depression was 22.4% for men and 29.7% for women according to Diagnostic and Statistical Manual for Mental Disorders, 3rd edition (DSM-III) criteria (Kivela et al., 1988). In the Berlin Aging Study (BASE), prevalence rates of 4.8% for major depression, 9.1% for all Diagnostic and Statistical Manual for Mental Disorders, 3rd edition Ð revised (DSM-IIIR) speci®ed depressive disorders and

26.9% of subthreshold depression were found. Similar prevalence rates were found in two Italian studies, but in patients with memory impairments and non-insulin dependent diabetes mellitus (Cosi et al., 1995; Amato et al., 1996). However, various studies have shown that there is a higher prevalence of depressive symptoms among women (Murrell et al., 1983; Berkman et al., 1986; Copeland et al., 1987; Kennedy et al., 1989) except that in a French study (Dufouil et al., 1995) probably due to the choice of di€erent cut-o€ scores of CES-D in males and in females. On the contrary, the prevalence rates of major depression in the community seems to be much lower, going from 1.7% in New Haven (Weissman et al., 1985), to 1.4% in female and 0.4% in male in the Epidemiologic Catchment Area (ECA) study (Weissman et al., 1988) up to 4.85% in the New York study (Potter et al., 1979). In these studies the Diagnostic Interview Schedule (DIS), previously described by Robins et al. (1981) was used. Other methods have been used in community studies in order to evaluate depressive disorders in the elderly (Weissmen and Myers, 1978; Uhlenlhuth et al., 1983; Ben-Arie et al., 1987; Carpiniello et al., 1989; Forsell et al., 1995). The prevalence rates found in these studies vary from 5.1% (Uhlenlhuth et al., 1983) to 14% (Carpiniello et al., 1989), according to the speci®city and sensitivity of the assessment methods and to the

Table 1 Prevalence of depressive symptoms in US and Europe community studies (from Lepine and Bouchez, 1998) Site

Author

n

Age

Methods of assessmenta

Prevalence (%)

US Durham County Los Angeles County Kentucky Washington New Haven New York New York Duke-EPESE

Blazer and Williams, 1980 Frerichs et al., 1981 Murrell et al., 1983 Goldberg et al., 1985 Berkman et al., 1986 Copeland et al., 1987 Kennedy et al., 1989 Blazer et al., 1991

997 126 2517 1144 Married women 2806 445 2317 3998

OARS, depression scale CES-Dr16 CES-Dr20 CES-Dr16 CES-Dr16 GMS-AGECAT CES-Dr16 Revised CES-D

New York City Tennessee

Potter et al., 1995 Okwumabua et al., 1997

1140 Adults 110

r65 r65 55+ 65±75 r65 r65 r65 65±74 75±84 r85 r65 Afro-Am.r60

CES-Dr16 CES-Dr16

14.7 16.7 F, 18.2; 9.5 F, 19.2; 16.2; F, F, 19.9; 8.1 10.3 12.3 11.4 19.8

Europe Liverpool London North London France

Copeland et al., 1987 Lindesay et al., 1989 Livingston et al., 1990 Dufouil et al., 1995

1070 890 811 2797

r65 r65 r65 r65

London Dublin

Prince et al., 1997 Kirby et al., 1997

654 1232

r65 r65

GMS-AGECAT CARE Dep. scale Short CARE M; CES-Dr17 F; CES-Dr23 Short CARE GMS-AGECAT

11.5; F, 14.3; M, 7.2 13.5 15.9 15.9 15.9 17 10.3; F, 11.3; M, 8.5

M, 13.7 M, 11.3 18.3; M, 13.0 M, 11.1

a CES-D, Center for Epidemiologic Studies Depression Scale; GMS-AGECAT, Automated Geriatric Examination for Computer Assisted Taxinomy Package; CARE, Comprehensive Assessment and Referral Evaluation.

P. Gareri et al. / Progress in Neurobiology 61 (2000) 353±396

place (i.e. community, residential care, hospital) (Table 3). In fact, in primary care, depressive symptoms are more frequent than in the community, varying from 15 to 30% in United States studies (Callahan et al., 1994; MacDonald, 1986) and from 21 to 37% in European studies (Evans and Katona, 1993) (Table 1). Rates of depressive symptoms about 20% (Kukull et al., 1986) and major depressive disorders rates around 13% (Koenig, 1991; Parmelee et al., 1989) were found in residential care or among instituzionalized patients. Some studies have reported no signi®cant di€erence between rural and urban population (Dufouil et al., 1995); however one study has found a higher risk for depression in an urban elderly population (Carpiniello et al., 1989). A peak in the incidence of depression has been reported in the years preceeding the retirement, followed by a low prevalence during the ®rst 10±15 years after retirement and an increased incidence after the age of 75 (Palsson and Skoog, 1997). To explain discrepancies between these results, several factors have been proposed. The use of the same structured diagnostic interviews as those used in younger people may be inadequate in the elderly. They require cognitive abilities (understanding, interpretation, memory) which often are deteriorated in elderly subjects and do not allow interviewers to facilitate remembering by commenting the items. Moreover, elderly subjects sometimes attribute their depressive symptoms to somatic disorders and these methods do not take into account, or even exclude, depressive disorders due to general medical conditions. Chronic

357

somatic diseases increase the risk of depression (Table 2), the severity and lenght of the mood disorder and induce poorer outcomes (Harlow et al., 1991). All these points may lead to an underestimate of major depression in the elderly, beside to increase the diculties of correctly diagnosing depression. Whatever the assessment method used, prevalence rates of depressive symptoms and major depression seem to be lower in elderly people in the community than in younger people. These results may be explained by a selective mortality bias (premature death of younger depressed subjects), a recall bias of psychiatric symptoms associated with cognitive problems, a more frequent denial of these symptoms by elderly subjects as compared with younger people, more prominence of physical symptoms of depression in aged people and a possible true cohort e€ect, as several studies have suggested that depression may be more prevalent in subjects born after World War II (Hasin and Link, 1988). Since there are marked di€erences in the symptomatology and causes of depression among young and elderly people, we'll report in more detail these aspects. 3. Symptomatology and aetiology of depression in the elderly Depressive disorder in younger people is often described as a tetrahedron of symptoms, where depressed mood, anxiety, reduced activity and somatic

Table 2 Associations between chronic diseases and initiation of antidepressant drug therapy (from Egberts et al., 1997)

Hypertension History of myocardial infarction History of stroke Diabetes mellitus Parkinson's disease Rheumatoid arthritis Osteoarthritis Glaucoma Cognitive impairment Number of visits to general practitioner during past year None (reference) 1±5 6±10 > 10 Number of drugs used None/one (reference) 2 3 r4 a b

CI = Con®dence interval; RR = Relative risk. Adjusted for age, sex and health-care resource consumption.

Crude RR (95% CI)a

Adjusted RR (95% CI)b

1.1 1.1 2.1 1.0 1.5 0.7 1.8 1.4 1.2

1.0 1.1 2.0 0.9 1.4 0.6 1.6 1.4 1.1

(0.9±1.5) (0.8±1.5) (1.1±4.1) (0.6±1.5) (0.7±3.4) (0.3±1.6) (1.4±2.3) (0.8±2.2) (0.9±1.6)

(0.8±1.3) (0.8±1.6) (1.0±3.9) (0.6±1.4) (0.6±3.1) (0.3±1.4) (1.2±2.0) (0.8±2.2) (0.8±1.5)

1 1.3 (1.0±1.7) 2.1 (1.4±3.2) 3.8 (24±6.2)

1 1.1 (0.8±1.4) 1.6 (1.0±2.4) 2.7 (1.6±4.3)

1 1.9 (1.4±2.7) 2.0 (1.4±2.8) 2.4 (1.8±3.2)

1 1.8 (1.3±2.5) 1.8 (1.3±2.5) 2.1 (1.6±2.9)

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symptoms are the four corners. In elderly people, we need to distinguish depressive illness from psychological disturbances secondary to other diseases (Table 2). Depression and such secondary disturbances often occur in the same patient in the elderly. In contrast to younger depressed patients, elderly patients often avoid reporting or showing that their mood level is lowered (Schulman, 1989) because they tend to hind their state of disease or, worse, they think that enjoying life less than before is an inevitable consequence of aging. Anxiety, worry, apprehension or panic that is out of proportion to an actual threat, tachycardia, tremor, hypoventilation and lightheadedness are common symptoms in the elderly, due to the activation of the autonomic system. Patients with anxiety may also complain of inner tremulousness and unsteadiness. The prevalence of anxiety among the elderly is estimated at around 15% (Katona, 1994), which is similar to that of depression; it is often found in elderly patients with major depressive disorder compared with younger depressive patients (Baldwin and Tomenson, 1995) and it is part of a depression±anxiety syndrome, in which either depressed mood or anxiety is the predominating symptom. In young people with major depressive disorder, retardation of activity, with slow, restricted and repetitive thoughts, is usually an obvious phenomenon. The same symptoms are also seen in elderly people, but may be more dicult to identify. Somatic disorder may reduce elderly people's activity, and tiredness and asthenia are very common symptoms in old age. These symptoms are often considered to be part of normal aging. Sleep disorders, reduced appetite and steady weight loss are frequent ®ndings in major depressive disorder. In younger people, the libido is often reduced, and impotence, frigidity and amenorrhoea may occur. In the elderly, reduced libido is not a very reliable symptom of depression, as people's sexual activity usually declines with aging. Besides, people of the older generation are usually unwilling to report these kinds of symptoms. Sleep disturbances are more readily reported, both as early awakening, and as frequent awakenings during the night. Loss of appetite and weight may be obvious. Depression in the elderly is often hidden behind somatic symptoms, either because of somatization of the disorder or because of accentuation of symptoms of a concomitant physical illness. One of the most common somatic symptoms is asthenia, followed by pain in di€erent parts of the body and reported as headache, abdominal pain together with constipation, pains at speci®c site, back pain, and also generalized pain in the body. Somatic functions are in¯uenced by depressive disorder. Elderly people seem to communicate these

somatic complaints more often than younger people. Worsening of the symptoms in the morning is not a regular feature in elderly depressive people with somatic complaints, but may be helpful in the di€erential diagnosis between a somatic disorder and depression. Cognitive impairment is usually caused by depression, but it may be aggravated by treatment with trycyclic antidepressants, especially in elderly people, so arising the need of a di€erential diagnosis between pseudodementia and predementia. In fact, patients with pseudodementia are often unwilling to undergo cognitive assessment, and they are usually aware of their memory de®cits, whereas demented patients lack this insight. Depression-related cognitive impairment is a condition that, despite initial treatment response, shows a progressive deterioration of cognitive functions in elderly people (Mitchell and Dening, 1996). Pseudodementia is often associated to major depression, masked by symptoms similar to Alzheimer's dementia. Moreover, thoughts and ideas are in¯uenced by depression; they become increasingly more pessimistic as the mood level drops. Hypochondriacal symptoms are common, and hallucinations sometimes occur in severely depressed elderly people. The content of both paranoid ideas and hallucinations is always in¯uenced by the depressed mood. Although the psychotic symptoms and hallucinations may suggest paranoid psychosis, the depressive nature of the psychosis reveals the underlying depression. As regards the etiology, heredity is the most important known cause of depression, even if it seems to be less important in the elderly. A number of hypotheses have been made, focusing that mood disturbances are probably linked to a disturbed central metabolism of monoamines 5-hydroxytriptamine (5-HT), noradrenaline (NA) and dopamine (DA) and most of the knowledge is derived from animal models. Many factors both in the young and in the elderly can in¯uence the onset of a depressed mood. For example, the metabolism of 5-HT and NA is reduced in the aging brain (Gottfries, 1990) and monoamine oxydase type B (MAO-B), which are enzymes catalyzing the oxidative deamination of DA as well as that of several exogenous amines, such as tyramine, are signi®cantly increased in the elderly. A marked disturbance of monoamine metabolism is also found in demented patients. Moreover, a close relationship was observed between depression and some concomitant physical diseases such as myocardial infarction, Cushing's syndrome, hypothyroidism and neoplasia (Gottfries, 1998). De®ciency in vitamin B12 and folate are linked to depressive disorders and can also in¯uence the treatment response to electroconvulsive therapy, antidepressants and tryptophan (Rey-

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359

Table 3 Some di€erent kinds of drugs may cause depression, especially in the elderly, where polypathologies often need a polypharmacotherapy Non steroidal anti-in¯ammatory drugs Analgesics Antihypertensive drugs Digitalis Sedative drugs Corticosteroids Antituberculotic drugs Antineoplastic drugs

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

nolds et al., 1970; Fava et al., 1997). De®ciency in these vitamins cause reduced activity of methionine synthetase, leading to accumulation of homocysteine and consequently, reduced formation of S-adenosylmethionine (SAM), which serves as methyl group donor in various transmethylation reactions. Furthermore, the risk of suicide increases with aging and it appears three-fold higher in elderly men than in general population (Finlayson and Martin, 1982; Charatan, 1979). A lot of drugs currently administered to elderly patients may induce an iatrogenic depression (Table 3). However, pharmacotherapy is fundamental in this group of patients, whose age-related physiological changes, concomitant diseases and drug treatment may alter the metabolic pro®le of antidepressant drugs (Greenblatt et al., 1982; Gerson et al., 1988; Potter et al., 1991). Even if use of psychotropic drugs in the aged population needs caution, when depression is readily diagnosed and, especially, treated, quality of life is clearly improved. A reduced compliance is often observed, probably due to cognitive disturbances, lack of understanding of the disease, presence of side e€ects preceeding the clinical response (Guarnieri and Sacchetti, 1998).

4. Age-related changes in pharmacokinetics and pharmacodynamics

The most important factors in¯uencing drug absorption in the aged are: (a) the increase in gastric pH, for the reduction in acid output following to gastric parietal cells decrease (Greenblatt et al., 1982). The increase in gastric pH increases basic drugs absorption and reduces that of acid drugs. Since antidepressants are weakly basic, they are quickly absorbed in the ®rst tract of small intestine, which is weakly acidic (pH = 6.6); (b) the reduction in gastrointestinal motility, with the consequent delayed gastric emptying (Galeotta et al., 1990); (c) the reduction in splancnic blood ¯ow for the diminished cardiac output (Safar, 1990); (d) the decrease in absorption surface. The distribution of a drug is in¯uenced by tissular blood ¯ow, plasmatic protein binding and the physicochemical properties of the drug itself (Galeotta et al., 1990). Moreover, it is in¯uenced by lean 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 lesser 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 action increases, thus causing the risk of iatrogenic e€ects in old people (Furlanut and Benetello, 1990;

4.1. Age-related changes in pharmacokinetics Age-related changes in pharmacokinetics and pharmacodynamics may cause an increase in adverse drug reactions (ADRs) in the elderly persons. In fact, aging causes a number of changes in drug absorption, distribution, biotransformation and elimination (Galeotta et al., 1990; Voltz and Moeller, 1994). Drug pharmacokinetics may change with age as a consequence of living habits in elderly subjects, such as diet, alcohol consumption, smoking, concomitant use of other drugs and genetic polymorphism of hepatic enzymes, diseases, etc. (Baumann, 1998) (Fig. 1).

Fig. 1. Factors in¯uencing the e€ects of a drug.

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Greenblatt et al., 1982; Montamat et al., 1989; Sanders-Bush and Sulser, 1995). Plasmatic binding proteins are albumin, a1-acid glicoprotein and lipoproteins. Aging causes a reduced synthesis of these proteins; in over 80 years old people albumin synthesis is 20% lesser than in a young adult, while is much far lesser in the elderly subjects a€ected by liver and/or renal failure (Table 4). These pathological conditions may both alter protein plasmatic 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, salicilic acid, phenytoin, etc., while a1-acid glicoprotein 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; Rubin, 1987); therefore, any change in plasmatic concentration of protein binding to antidepressants might in¯uence their distribution and concentration to receptor sites. For example binding of imipramine to lipoproteins was shown to be in hyperlipoproteinemic patients superior to that one in normal persons; this means that all those drugs which can in¯uence lipoprotein plasmatic concentration might also in¯uence antidepressant distribution. As regarding to imipramine binding to a1-acid glicoprotein, no di€erence was seen among young and old adults, while the results appear to be controversial for amitryptiline and desipramine (Wallace and Werbeeck, 1987). Another crucial point in drug kinetic is its biotransformation. Liver clearance of a drug mainly depends on liver blood ¯ow, which as we know decreases with aging, and on liver enzyme activity. The latter depends on phase 1 and phase 2 reactions. In phase 1 reactions the involved enzymes are called mixed function oxidase, composed by a number of hemoproteins, such as citocrome-P450, citocrome b5 and a ¯avoprotein, Nicotinamide dyphosphonucleotide hydrogenase (NADPH)-citocrome-C-reductase. Phase 2 reactions involve acetylation and conjugation reactions with glycuronic acid; while these reactions are not in¯uenced by age, phase 1 ones are strongly in¯uenced by aging, sex and genetic factors. In fact, the existence of a gen-

etic polymorphism in the oxidative metabolism of some drugs, such as antidepressants and b-blockers was shown (Alexanderson et al., 1969; Galeotta et al., 1990; Clark, 1985); therefore, genetic mutations inherited as recessive autosomic character might cause a reduced synthesis of various citocrome-P450 isoenzymes (now named as CYP2D6, CYP1A2, CYP2C9/ 19, CYP3A4) (Table 5, see below). This means that for a given substance, i.e. the prototype debrisoquine, an experimental antihypertensive drug, there are fast (90% of the individuals) and slow metabolizations (10%, that is the mutants) (Bertilsson et al., 1993). 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 citocrome-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 show that nortryptiline plasmatic concentrations were equal in monozygotic, while were di€erent in dizygotic. Furthermore, even in the monozygotic twins the concentrations could be di€erent if one was at the same time treated with other drugs. In fact, liver metabolism may also be in¯uenced by smoke, liver diseases, alcohol, nutritional status and, especially in the elderly, concomitant administration of more drugs. The latter condition is important because drugs may increase or reduce microsomial enzymes metabolizing drugs. The former are called inductors, the latter inhibitors. Liver metabolism of a drug can also be reduced by another drug by competing with the same enzyme system. 4.1.1. Genetic polimorphism of hepatic enzymes A particular role for the metabolism of a drug, both in adults and in elderly people is due to isoenzymes of cytochrome P-450. In man more than 30 isoenzymes of cytochrome-P450 were identi®ed; CYP1A2, CYP2C9/19, CYP2C9, CYP2D6 and CYP3A4 are important in the metabolism of a number of antidepressants (Table 5), especially selective serotonin reuptake inhibitors (SSRI) and of other drugs (Brunello, 1998). A genetic polimorphism has been described for two of

Table 4 Age-related pharmacokinetic changes Variables

Young adults (20±30 years old)

Old adults (60±80 years old)

Body water (% body weight) Thin mass (% body weight) Body fat (% body weight)

61 19 26±33 (Women) 18±20 (Men) 4.7 100 100

53 12 38±45 36±38 3.8 80 55±60

Seric albumin (g/dl) Kidney weight (% of young adults) Liver blood ¯ow (% of young adults)

± ± ± ± ± Fluvoxamine

Carbamazepine Dexomethasone Rifampicin, Phenytoin Omeprazole Thioridazine, Quinidine, Fluoxetine, Paroxetine, Sertraline Erythromycin, Grapefruit juice, Itraconazole, Ketoconazole, Omeprazole

Smoking, Omeprazole Fluvoxamine

± ± Yes CYP 2CA CYP 2E1 CYP 2C19

± ± 2±3% white people, 15±25% oriental people

Possible CYP 3A4

±

Yes Yed CYP 2a1q CYP 2D6

3±5 5±8% white people less in oriental people

Possible CYP 1A2

±

Ca€eine, Imipramine, Clomipramine, Antipyrine, Theophylline, Clozapine, 17-boestradiol, demethylation of TCAs Mephenytoin, Debrisoquin, Dextromethorphan, Sparteine, Hydroxylation of Nortriptyline, Desipramine, ¯uvoxamine Midazolam, Some benzodiazepines, Cyclosporin A, Calcium channel blockers, demethylation of TCAs, citalopram, venlafaxine, ± ± Demethylation of TCAs Citalopram, Meclobemide

Inducers Inhibitors Percentage poor metabolizers Typical substrates Genetic polymorphism Isoenzyme

Table 5 Isoenzymes of cytochrome P-450 involved in the metabolism of SSRIs (from Bauman, 1998, modi®ed)

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them, CYP2D6 and CYP2C19 and two phenotypes have been identi®ed, poor metabolizers (PM) and extensive metabolizers (EM) (Gonzalez et al., 1988; DeVane, 1994). Therefore, all the patients presenting a genetic de®ciency of these enzymes may undergo a higher risk of adverse e€ects when they are treated with a drug which is a substrate of these isoforms (Brosen, 1996; Baumann, 1996). On the other hand, the discovery of a gene ampli®cation for CYP2D6 may explain the existence of ultrarapid metabolizers (Bertilsson et al., 1993). Isoenzymes of CYP1A2 and CYP3A4 have shown a high interindividual variability in their activity, which may be induced by some exogenous factors, such as smoke and drugs (barbiturates) (Table 5). Moreover, CYP2D6 is the cytochrome whose polymorphism was better studied. The activity of this isoenzyme is de®cient or absent in 5±8% of white people and 2±5% of black and oriental people. This cytochrome is involved in the metabolism of desipramine, nortriptyline, imipramine, amitriptyline and clomipramine and also of other drugs such as antipsychotics (risperidone, clozapine), antiarrythmic drugs (propaphenon) and b-blockers. Recent studies have shown that some SSRIs can in vitro inhibit the activity of CYP2D6 (Crewe et al., 1992). The most powerful inhibitor seems to be paroxetine, followed by ¯uoxetine, nor¯uoxetine and sertraline. Citalopram, ¯uvoxamine are weak inhibitors (Jeppesen et al., 1996). Venlafaxine and nefazodone do not inhibit this cytochrome (Ereshefsky, 1996; Barbhaiya et al., 1996) (Table 5). CYP1A2 plays an important role in oxidative metabolism of ca€eine, theophylline, some Tricyclic antidepressants Depression Scale (TCAs) (amitriptyline, imipramine, clomipramine); it is inhibited by ¯uvoxamine. CYP2C9/19 is responsible for demethylation of diazepam and TCA's tertiary amines. At last CYP3A4 is important for the metabolism of short half-life benzodiazepines (BDZ) such as triazolam, some calcium antagonists, immunosoppressors (cyclosporine), erythromicine and other macrolides, some TCAs, sertraline, citalopram and it represents a secondary metabolism pathway for venlafaxine (Brunello, 1998) (Table 5). Aging also causes a reduced drug renal excretion; this even occurs in the absence of overt renal failure, because glomerular ®ltration in old people is 30±35% less than young adults and tubular function and renal blood ¯ow are compromised too (Lamy, 1986). Drugs which are excreted through glomerular ®ltration and are potentially toxic are digoxin, lithium, aminoglycosides, procainamide, cimetidine, chlorpropamide, etc. Moreover, in the elderly a normal serum creatinine does not mean a good glomerular ®ltration, or rather it can be misleading because it will be slowed in individuals with decreased muscle mass. Therefore, we

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need to determine creatinine clearance (CLCR) and a fast way is given by a formula which calculates it according to serum creatinine, age and weight, even if it is not as preferable as direct determination based on 24 h urine collections (Beers and Ouslander, 1989; Montamat et al., 1989; Friedman et al., 1989): Creatinine clearance ˆ

…140 ÿ age in years†  body weight …kg† 72  plasma creatinine

4.2. Age-related changes in pharmacodynamics In the elderly some drugs may determine di€erent pharmacological e€ects than in the young for various reasons, ®rst of all for the changes in the number of receptors and in binding anity and the de®cits in homeostatic mechanisms, that is all the hormonal, biochemical and nervous compensatory re¯exes limiting a drug e€ect (Montamat et al., 1989; Swift, 1987). So, for example, in an old individual, you may have a hortostatic hypotension following to the administration of an antihypertensive drug, for the reduced autonomic functions. Another point is due to polypathologies which can even alter pharmacological response. All these changes have to be taken into account and so that we can realize why, for example, old people are more sensitive to benzodiazepine e€ects, having a stronger sedation even for plasma concentrations of these drugs inferior to

those ones which a young man needs for having a sedative e€ect. In other words whatever is therapy in an old man, we need to be careful, trying to get an ecacious pharmacological response with the lowest dosage. 5. Mechanism of action of antidepressants The underlying biochemical events in endogenous depression are still unknown. A disregulation of the Central Nervous System (CNS) involving the neurotransmitters NA, 5-HT and DA has been suggested and the mainstream of research in depression has principally focused on NA and 5-HT systems as having many drug development programmes. Currently, the most ecacious treatment of major and related depression, obsessive compulsive disorders and panic attacks is considered to be an increase in 5-HT neurotransmission, e.g. by inhibition of 5-HT uptake, although increase in NA neurotransmission may be necessary as well (Brunello et al., 1994/1995; Hyttel, 1994; Murphy et al., 1995). Tricyclics (TCAs) either a€ect both the uptake of NA (Fig. 2) and 5-HT (Fig. 3), or NA alone which is also the case for the reversible inhibitors of monoamine oxidase (RIMAs). Serotonin reuptake inhibitors (SSRIs) preferentially act as inhibitors of 5-HT uptake with only slight or no e€ect on NA uptake. The potency and selectivity of a series of SSRIs in comparison with clomipramine `classical' antidepressant are shown in Table 6. It appears that the series covers approximately 6 decades, with

Fig. 2. Schematic representation of antidepressant drugs acting on noradrenergic neurotransmission.

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363

Fig. 3. Schematic representation of antidepressant drugs acting on serotoninergic neurotransmission.

the most selective SSRI, citalopram, being 3400 times more potent on 5-HT than on NA uptake and the most selective NA uptake inhibitor Ð maprotiline Ð being 660 times more potent on NA than on 5-HT uptake. Clomipramine is the only TCA with a ratio greater than 1 (Hyttel and Larsen, 1985). Citalopram is 240 times more selective than clomipramine, whereas ¯uoxetine is only slightly more selective than clomipramine (Hyttel, 1982; Hyttel and Larsen, 1985). Potency and selectivity do not coincide as can be seen from Table 6, e.g. sertraline versus citalopram and desipramine versus maprotiline. Some of the most selective SSRIs have been radio-

labelled and used in various studies as ligands for the uptake site (Mellerup et al., 1983; Raisman and Langer, 1983; D'Amato et al., 1987; Plenge and Mellerup, 1991). Similarly, a series of selective NA uptake inhibitors, e.g. desipramine (Langer et al., 1981; Raisman et al., 1982) and selective DA uptake inhibitors, e.g. GBR 12935 (Andersen, 1987), have been radiolabelled to be used as ligands for the NA and DA uptake sites, respectively. SSRIs have high anity for the sites labelled with citalopram and paroxetine but no or very low anity for the sites labelled with desipramine and GBR 12935 in accordance with the characterization of these sites

Table 6 Binding anity of SSRIs and clomipramine on various receptor subtypes (Ic50 values, nM)

3

H-ligand Citalopram Sertraline Paroxetine Fluvoxamine Fluoxetine Clomipramine

5-HT1A

5-HT2A

5-Ht2C

a1

a2

b

H1

ACh

8-OH-DPAT 15000 100000 > 100000 > 100000 79000 28000

Ketanserin 5600 8500 18000 12000 710 54

LY 278584 630

Prazosin 1600 2800 19000 4800 14000 60

Idazoxan 18000 1800 8900 1900 2800 1800

Dihydro-alprenolol > 100000 1400 35000 89000 18000 22000

Mepyramine 350 10000 19000 11000 3200 54

QNB 5600 1100 210 34000 3100 67

20000 6700 1600

Hippocampus, septum, amygdala, hyperpolarization, raphe nuclei widespread distribution, vasoconstriction, blood vessels Globus pallidus, substantia nigra, inhibition neuro-tranwidespread distribution, mitter and neuropeptide, cranial blood vessels release; vasoconstriction Trigeminal ganglia, inhibition neuropeptide release Caudate putamen, amygdala, unknown frontal cortex, globus pallidus Prefrontal cortex, claustrum, depolarization; cerebral cortex, tuberculum olsmooth muscle con-factorum, striatum, n. accumbens, traction; platelet aggregaventral pallidum, pedunculotion latero dorsal tegmental n.; vascular smooth muscle cells, platelets Stomach fundus, endothelium, fundus contraction of blood vessels, colon, small intestine; only recently detected in brain using antibodies Choroid plexus, very widespread distribution in forebrain± midbrain±hindbrain food intake spinal cord, not in periphery

5-HT1A

Basal ganglia, striatum, n.accumbens Increase neurotransmitter intestinal myenteric plexus, heart release, gastrokinetic e€ects positive inotropic e€ects mRNA in: cortex, hippocampus, Unknown habenula, olfactory bulbs, cerebellum Immunocytochemistry: glial cells Immunocytochemistry: tuberclm olfactorium, Unknown n. Unknown accumbens, striatum, frontal, enthorinal cortex, hippocampus, cerebellm Hypothalamus, thalamus, hippocampus, Phase advancement of brain stem, cortex; Intestinal and vascular circadian rhytm; hypotension, smooth muscle smooth muscle relaxation

5-HT4

5-HT7

5-HT6

5carboxamidotryptamine, 8-OHDPAT

LSD

aCH3-5-HT

Ritanserin, MDI 100907, ketanserin, risperidone, olanzapine, sertindole, clozapine, pipamperone

Ocaperidone (non selective) Unknown

Gr127935 (partial agonist)

WAY100635 (silent)

Antagonist

Several antipsychotics (see Fig. 2)

Several antipsychotics (see Fig. 2) antidepressants

SB200646A, SB206553,SB204741, LY266097, BW723686 Antagonist for anxiety, DimethoxyRitanserin, mesulergine, panic attacks; increase phenylisopropymianserin, olanzapine, lamines; metachloro clozapine, sertindole, zotepine, phenyl-piperazine(mCPP) ziprasidone Antagonist for chemo-radio- 2-CH3-5HT, and m-ClBRL46470, MDI72222, therapy-induced emesis phenyl biguanide Y25130,GR65630, tropisotron, odansetron, granisetron Agonists for gastrokinetic Cisapride, renzapride RS39604, SB203186, stimulation SB204070, GRI13808, LY297582 Unknown Unknown Unknown

Wide central and peripheral occur Depolarization rence on neuronal cells; area postrema, n, tractus solitarius, substantia gelatinosa, trigeminal n., dorsal vagal complex

5-HT5A(5B)

Sumatriptan Unknown

Sumatriptan; alm.

8-OHDPAT

Agonist

Antagonists for dysthymia, Dimethoxyphenylnegative symptoms of isopropylamines schizophrenia; Impaired blood pontine n., circulation

Agonist for migraine Unknown

Post-synaptic agonists; autoreceptor antagonists for anxiety-depression Antagonist for depression ; agonist for migraine

Disease therapy

5-HT3

5-HT2C

5-HT2B

5-HT2A

5-HT1D 5-HT1B

5-HT1B

Physiological response

Brain area of highest density

Table 7 Features of 5-HT receptor subtypes

Increase cAMP

Increase cAMP

Decrease cAMP

Increase cAMP

Pentameric cation channel permeable to Na+, K+, Ca++

Rise in IP3, arachidonic acid, intracellular Ca++

Rise in IP3

Rise in IP3 arachidonic acid, intracellular Ca++

Decrease cAMP Decrease cAMP

Decrease cAMP

Decrease cAMP open K+ channels

2nd messenger response

364 P. Gareri et al. / Progress in Neurobiology 61 (2000) 353±396

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to represent the binding site for the 5-HT, NA and DA transporter, respectively. The binding site measured using imipramine as ligand represents binding to both the 5-HT and the NA transporter (Table 6). ‰3 HŠ Citalopram is a very selective ligand for the 5HT transporter (Table 6). This is in accordance with results obtained by D'Amato et al. (1987), who found a very high correlation between citalopram binding and ‰3 HŠ 5-HT uptake data …r ˆ 0:97). Apparently, imipramine, paroxetine and citalopram bind to di€erent areas of the 5-HT transporter; citalopram probably binds only the 5-HT speci®c part. Plenge et al. (1991) have demonstrated that di€erent SSRIs in¯uence di€erently the dissociation rate of the three ligands to their respective binding sites. In this respect, citalopram and clomipramine di€er signi®cantly from the other SSRIs. Since the e€ects of metabolites play a role in experimental and clinical e€ects of antidepressants, especially for those drugs which give rise to high levels of pharmacologically active metabolites (see below) the implications of binding of the single compound without its active metabolites must be considered with particular attention. In addition, the possibility that a speci®c interaction with one or more 13 mammalian 5-HT receptor subtypes must be considered (Table 7). In the last decade, several 5-HT receptor subtypes have been discovered by gene cloning. Human genes have been cloned for all 13 mammalian 5-HT receptor subtypes, variants and splice variants have been reported (see Hoyer et al., 1994; Hoyer and Martin, 1996). During repeated administration most tricyclic antidepressants (TCAs), MAO inhibitors (MAOIs) and electroconvulsive shock down-regulate the NA-coupled adenylate cyclase system in the brain. Generally this down-regulation is linked to a reduction of the density of b-adrenoceptors (Sulser and Mishra, 1982). The e€ects of SSRIs on b-adrenoceptors density in experimental animals are inconsistent. Citalopram and paroxetine do not down-regulate b-adrenoceptors, whereas either no e€ect or a down-regulation is seen after repeated administration of ¯uoxetine, ¯uvoxamine and sertraline. In general, SSRIs do not in¯uence a1- or a2-adrenoceptors upon repeated treatment, although increase in the density of a1-adrenoceptors, as seen after TCAs and electroconvulsive treatment, has been observed after repeated administration of citalopram (Vetulani et al., 1984). An increase in dopaminergic function has been observed after TCAs and SSRIs, as in behavioural studies (Maj et al., 1989). Like other antidepressants, citalopram reduced D1 receptor number (Klimek and Nielsen, 1987) but left D2 receptor number unchanged. The e€ects of other SSRI on DA receptors remains to be elucidated. Although an in¯uence on the dopamin-

365

ergic system might raise the question of a dependence or abuse potential, several studies clearly produce evidence against this, e.g. citalopram does not induce stereotypy in rats as observed after d-amphetamine and methylphenidate (Hyttel et al., 1988), citalopram does not generalize to the discriminative stimulus properties induced by d-amphetamine (Hyttel et al., 1988). 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a 5-HT1A receptor agonist, N-(3-tri¯uoromethylphenyl)piperazine (TFMPP), a 5-HT receptor agonist or d-lysergic acid diethylamide (d-LSD), a 5-HT receptor agonist and potent hallucinogen (Arnt, 1989) in rats or by the 1-[2-[bis(4-¯uorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine (GBR 12909), a DA uptake inhibitor, in squirrel monkeys (Melia and Spealman, 1991). Chronic administration of TCAs and SSRIs enhances 5-HT neurotransmission in hippocampus as shown in electrophysiological studies (Blier et al., 1990): TCAs by development of supersensitivity of postsynaptic 5-HT1A receptors, whereas for SSRIs it is a consequence of a subsensitivity of somatodendritic and terminal 5-HT autoreceptors of the 5-HT1B or 5HT1D subtypes. TCAs consistently down-regulate 5-HT2A receptors in the rat frontal cortex whereas the e€ects of SSRIs is less consistent (for review see Johnson, 1991). Behavioural studies however indicate that SSRIs, e.g. ¯uoxetine, citalopram and paroxetine reduce the responsiveness of 5-HT2A receptors. The clinical implication of this observation is questionable since electroconvulsive shock treatment up-regulates these 5-HT receptors. There are several subtypes of 5-HT receptors having important clinical implications. 5.1. 5-HT receptors From the mid-70s to the mid-80s, radioligand binding, signal transduction assays and functional e€ects in tissues and in vivo have been used to identify and characterize 5-HT receptor subtypes. This led to the identi®cation of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C (previously called 5-HT1C), 5-HT3 and 5-HT4 receptors. In the last decade, several new subtypes have been discovered by gene cloning (see Table 7). Today, 13 mammalian 5-HT receptors are known. Human genes have been cloned for all of them and for several subtypes, variants and splice variants have been reported (Hoyer et al., 1994; Hoyer and Martin, 1996). Twelve of the 5-HT receptors belong to the superfamily of G-protein-coupled receptors, whereas the 5-HT3 receptor is a ligand-gated cation channel. The 5-HT receptor subtypes and their main individual features are listed in Table 7. The most important of the 5-HT receptor subtypes with regard to the action of current antidepressants is the 5-HT2A receptor. All the newer

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antidepressants are relatively potent 5-HT2A antagonists. 5-HT2A receptor localization in mammalian brain has been extensively studied by means of radioligand autoradiography (Pazos et al., 1985), in situ hybridization of mRNA (Mengod et al., 1990) and immunocytochemistry (Morilak et al., 1993). 5-HT2A receptors occur mainly in the telencephalon and much less in the midbrain and hindbrain. They are also present on vascular smooth muscle cells. In many brain areas they are localized on g-Aminobutyric acid (GABA)-ergic cells, e.g. the olfactory nucleus, bulbus and tuberculum, the cerebral cortex (layers II±IV), claustrum, hippocampus (CA1 pyramidal cells), nucleus accumbens and ventral pallidum. In some areas they occur on cholinergic cells: neostriatum, pedunculopontine nucleus, and latero-dorsal tegmental nucleus. The most selective known 5-HT2A antagonist is MDL10090. Ritanserin is a combined 5-HT2A/5-HT2C antagonist. The pharmacological e€ects of 5-HT2A antagonists are well documented. The most important clinical ®ndings attributed to 5-HT2A antagonism are improvement of negative symptoms in patients with schizophrenia (Davis and Janicak, 1996), enhancement of cognition and possibly attenuation of extrapyramidal symptoms induced by dopamine D2 antagonism (Bersani et al., 1990). A possible explanation for the bene®cial e€ects of 5-HT2A antagonism in schizophrenia can be found in electrophysiological and neurochemical studies. 5-HT2A antagonists decrease GABA-ergic activity. They block the 5-HT-induced excitation of GABA-ergic interneurones in the pyriform and the frontal cortex (Gellman and Aghajanian, 1994) and of GABA-ergic cells in the diagonal band of Broca and in the medial septum. By reducing inhibitory GABA-ergic transmission, 5-HT2A antagonists may disinhibit glutamatergic transmission. This is of particular importance for cortical glutamatergic e€erents which are under inhibitory control of cortical GABA-ergic interneurones. Facilitation of glutamatergic action is therefore probably involved in the therapeutic action of 5-HT2A antagonists (Gellman and Aghajanian, 1994). Indeed, electrophysiological studies have shown that excitatory 5-HT2A receptors and inhibitory 5-HT1A receptors co-exist on cortical cells (Ashby et al., 1994). In vivo studies with systemic drug administration have shown that 5-HT2A receptors have a role in the regulation of noradrenergic and dopaminergic cell ®ring by way of an indirect route through GABA-ergic and glutamatergic neurones. Chiang and Aston-Jones (1993) demonstrated that activation of 5-HT2A receptors by systemic administration of 5-HT2A agonists decreased spontaneous discharge of locus coeruleus neurones (mediated by GABA-ergic neurones) and

increased responses evoked by somatosensory stimulation (involving glutamatergic inputs to the locus coeruleus). 5-HT2C receptors have a very widespread distribution in the central nervous system (CNS). They are abundant in the telencephalon, the midbrain, the hindbrain, the cerebellum and the spinal cord. The most dense occurrence of radioligand binding sites is in the choroid plexus (Abramowski et al., 1995). Several antipsychotics (such as sertindole, zotepine, ziprasidone, clozapine, olanzapine) have relatively potent 5-HT2C antagonist activity, as do some antidepressants (such as mianserin and some tricyclic antidepressants), but no suciently selective agonists or antagonists are available today. Animal and human pharmacological studies with non-selective agents point to a possible role of 5-HT2C receptors in anxiety. The 5-HT agonist, m-chlorophenylpiperazine, induces anxiety in rats and mice and elicits panic attacks in humans. These e€ects are antagonized by 5-HT2C antagonists with potencies which correlate with their 5-HT2C receptor anities. 5HT2C receptors also have a role in the regulation of food intake. A reduction in food intake induced by mchlorophenylpiperazine or fen¯uramine is reversed by 5-HT2C antagonists. Dieting, accompanied by low tryptophan intake, causes 5-HT2C receptor supersensitivity. Hence 5-HT2C receptor blockade may lead to substantial weight increase. This indeed is a side-e€ect of antipsychotics and antidepressants with potent 5HT2C antagonism. 5-HT2C receptors also have a role in development, in cell growth and di€erentiation and they modulate endocrine functions. 5-HT2C receptor blockade can attenuate prolactin release (Coccaro et al., 1996). Other roles, related to the widespread distribution of 5-HT2C receptors throughout the brain and spinal cord, are not understood. 5-HT6 receptors were discovered by gene cloning. Immunocytochemical studies (Gerard et al., 1997) have revealed that the density of these receptors is highest in the olfactory tubercle, nucleus accumbens, striatum, frontal and entorhinal cortex, the hippocampus (CA1 area, dendate gyrus) and the molecular layer of the cerebellum. They occur at moderate density in the thalamus, substantia nigra reticulata, superior colliculus, the motor trigeminal nucleus, and the facial nucleus. Immunoreactivity of the protein matches mRNA distribution, suggesting localization on dendritic processes. No selective 5-HT6 agonists or antagonists are known, although LSD and some antipsychotics (sertindole, olanzepine, zotepine, clozapine, ziprasidone) show high anity for 5-HT6 receptors. The physiological, pharmacological and pathological role of these receptors remains enigmatic. 5-HT7 receptors were also originally detected by gene cloning. They are abundant in the medial thalamic nuclei, the molecular layer of the dendate gyrus,

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the entorhinal cortex and cortical layers II±IV and the amygdala. They occur at a moderate density in the hippocampus (CA1, CA2, CA3), septum, hypothalamic nuclei, claustrum, ventral pallidum, globus pallidus, superior colliculus, substantia nigra reticulata, dorsal raphe nucleus and locus coeruleus (To et al., 1995). No selective 5-HT7 receptor agonists or antagonists are known. 5-HT7 receptors appear to be prone to down-regulation: hypothalamic 5-HT7 receptor binding sites are reduced after 21 days treatment with the 5-HT re-uptake blocker, ¯uoxetine. 5-HT7 receptors seem to mediate the 5-HT-induced phase shifting in the circadian rhythm of melatonin secretion (a 5HT agonist e€ect mimicking the e€ect of light). The signi®cance of 5-HT7 receptor blockade with regard to antidepressant drug action remains to be elucidated. 5.2. Adrenoreceptors The adrenoreceptors subtypes are usually named as a and b. 5.2.1. a-Adrenoceptors It is well know that pre- and post-junctional a-adrenoceptors had di€erent pharmacologic characteristics (Starke et al., 1974; Langer, 1974). Langer (1974) suggested the designation of a1- and a2-adrenoceptors for post-junctional and pre-junctional a-adrenoceptors, respectively. Although most vascular contraction is mediated by a1-adrenoceptors, certain vessels or vascular beds have post-junctional a2-adrenoceptors that also mediate a contractile response. In addition to the pre-junctional control of NA release from the neuronal varicosity, a2-adrenoceptors mediated functions as platelet aggregation and inhibition of insulin secretion. Potent and highly selective agonists and antagonists have now been identi®ed for both a1 and a2-adrenoceptors. With the advent of new techniques for studying drug-receptor interactions, such as radioligand binding assays, the ability to isolate and purify receptor proteins, it has become clear that there are multiple subclasses of both a1- and a2-adrenoceptors (Ru€olo, 1991; Nichols and Ru€olo, 1991; Bylund, 1992). Currently, molecular biology techniques have identi®ed three distinct subtypes of both a1- and a2-adrenoceptors by using radioligand binding techniques (Bylund, 1992). Furthermore, apparently independent of this subclassi®cation scheme, a1- and a2-adrenoceptors can be pharmacologically subclassi®ed based on the ability of certain antagonists to block the action of NA (or other agonists) (Muramatsu et al., 1990; Nichols and Ru€olo, 1991). a1- and a2-adrenoceptors utilize di€erent signal transduction processes to translate receptor occupation by an agonist to a functional cellular response. a1adrenoceptor activation increases intracellular calcium

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concentrations. The activation of a2-adrenoceptors is consistently associated with inhibition of adenylate cyclase. However, this does not necessarily represent the mechanism for a2-adrenoceptor signal transduction in all tissues. Both a1-adrenoceptor-mediated calcium e€ects and a2-adrenoceptor-mediated inhibition of adenylate cyclase involve a guanine nucleotide regulatory protein (G-protein) that binds guanine nucleotides and acts to convey the signal from the receptor to the catalytic unit responsible for calcium translocation or adenylate cyclase inhibition, respectively. Molecular biologic studies have clearly demonstrated that the Gprotein interacts with the third intracellular loop of the a-adrenoceptor. Many distinct G-proteins have been identi®ed and subtle changes in amino acid sequence in the third intracellular loop of the a-adrenoceptors can in¯uence both the eciency of coupling between the receptor and G-protein as well as which G-protein interacts with the receptor (Stadel and Nakada, 1991). Interestingly, the third intracellular loop represents the region of least homology between the a-adrenoceptor subtypes. a1-adrenoceptor-mediated elevation in intracellular calcium concentration is often a result of calcium release from intracellular stores; it occurs through a G-protein-mediated activation of phospholipase C. This enzyme hydrolyzes phosphatidylinositol4,5-bisphosphate to generate inositol-1,4,5-triphosphate, which acts, in turn, to release intracellular calcium stores from the sarcoplasmic reticulum and dyacylglycerol, which activates protein kinase C. However, other a1-adrenoceptor-mediated responses depend on the in¯ux of extracellular calcium through voltagegated calcium channels. Activation of a2-adrenoceptors results in the inhibition of adenylyl cyclase activity, mediated through an inhibitory G-protein (Gi) (Limbird, 1988). a2-adrenoceptors have been shown to activate other potential signal transduction mechanisms, including potassium channels, phospholipase A2 and Na+/H ' exchange. 5.2.2. b-adrenoceptors In 1967, Lands et al. (1967) comparing rank orders of potency of agonists, concluded that there were two subtypes of the b-adrenoceptor. The b1-adrenoceptor, the dominant receptor found in hearth and adipose tissue, was equally sensitive to NA and adrenaline, whereas the b2-adrenoceptor, responsible for relaxation of vascular, uterine and airway smooth muscle, was much less sensitive to NA vis-a-vis adrenaline. Selective agonists and antagonists of b1- and b2- adrenoceptors have been identi®ed, and several of these drugs have been utilized extensively as therapeutic agents. Evidence has accumulated over the years for the existence of an `atypical' b-adrenoceptor that is insensitive to the commonly used antagonists. Selective agonists are now available for this receptor, now commonly

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known as the b3-adrenoceptor. These agents may o€er novel therapeutic opportunities through their action at b3-adrenoceptor on the adipocyte or pancreatic islet cell. Genes encoding the three b-adrenoceptors have been cloned and expressed; the pharmacologic characteristics of the puri®ed receptors obtained in this manner corresponds well with those of the three badrenoceptor subtypes identi®ed in native tissues. The molecular pharmacology of the b-adrenoceptors has been studied extensively. The b2-adrenoceptor was the ®rst adrenoceptor to be cloned, and the analysis of the hydrophobicity of the 418 amino acids making up its sequence suggested a folded structure passing through the cell membrane seven times, with an extracellular amino terminus and intracellular carboxyl terminus (Dixon et al., 1986). All three b-adrenoceptor subtypes appear to be linked to adenylyl cyclase activation through a stimulatory G protein (Gs) with no evidence for subtype-related di€erences in receptor±cyclase interaction. The badrenoceptors have been the prototype for studies on the linkage between receptor, G-protein, and the catalytic subunits of adenylyl cyclase, and much is known regarding the molecular interactions between these three proteins (Stadel and Nakada, 1991). There is evidence to suggest that in certain tissues, such as cardiac muscle, there could be a direct coupling between Gs and a voltage-sensitive calcium channel (Yatani et al., 1987). 5.3. Dopamine receptors Dopaminergic neurons are localized mainly in the substantia nigra pars compacta, the ventral tegmental area and the hypothalamus. They de®ne three main pathways, the nigrostriatal, the mesolimbic and the tuberoinfundibular. Since selective radioligands capable of discriminating each member of the dopamine receptor family are unavailable, the study of dopamine receptor distribution in the brain by classic autoradiography binding techniques has been dicult. Thus, in situ hybridization has been used extensively as the method of choice to localize the various receptor mRNAs. The study of the distribution of dopamine receptor is of great interest, since it can shed light on the distinct roles of the individual subtypes in controlling the multiple brain functions with which dopamine is associated. The D1 receptor is the most widespread dopamine receptor and is expressed at a higher level than any other dopamine receptor (Fremeau et al., 1991; Weiner et al., 1991). D1 mRNA is found in areas known to be under dopaminergic control such as the striatum, nucleus accumbens, and olfactory tubercle. It is also found in the limbic system, hypothalamus and thalamus. In other areas with numerous binding sites for

the D1 receptor, no mRNA is detected, suggesting that in these areas the D1 receptor is present in projections only. This is the case in the entopeduncular nucleus, globus pallidus and in the substantia nigra pars reticulata, where D1 dopamine receptors originate from striatal GABAergic neurons co-expressing substance P (Le Moine et al., 1991). The D5 receptor is expressed at a much lower level than the D1 receptor, and shows a distribution restricted to the hippocampus and to two sets of nuclei: the lateral mamillary nucleus and the parafascicular nucleus of thalamus (Tiberi et al., 1991; Meador-Woodru€ et al., 1992). Interestingly, the D1 receptor mRNA shows no signi®cant expression in these nuclei. Moreover, these regions are not detected by radioligand binding, suggesting that the D5 receptor is either translocated axonally to other brain regions or that its level of expression is too low to be detected by standard binding procedures. The D2 receptor has been found mainly in the striatum, olfactory tubercle and nucleus accumbens where it is expressed by dopaminoceptive GABAergic neurons co-expressing enkephalins (Le Moine et al., 1990; Le Moine and Bloch, 1995). It is also found in the substantia nigra pars compacta and in the ventral tegmental area, where it is expressed by dopaminergic neurons (Meador-Woodru€ et al., 1989; Weiner et al., 1991). Thus, the D2 dopamine receptor is found at both pre- and post-synaptic levels in the brain. The D2 receptor has long been known to be expressed in the pituitary (Creese et al., 1977; Caron et al., 1978) where it regulates the production and the secretion of PRL. The D3 receptor has received much attention, mainly because of its speci®c distribution in limbic areas such as the shell of the nucleus accumbens olfactory tubercle and islands of Calleja, and its low expression in the striatum (Sokolo€ et al., 1990; Bouthenet et al., 1991). More precisely, the D3 mRNA was found mainly in the ventral striatal complex, the substantia nigra pars compacta, the ventral tegmental area and the cerebellum (Diaz et al., 1995). In the islands of Calleja, both D3 receptor binding and messenger RNA are abundant in the entire population of granule cells, which are known to make sparse contacts with dopaminergic axons. The distribution of the D3 receptor is of interest since, as we will discuss later, neuroleptics that show high anity to D3 receptor seem to induce less extrapyramidal side e€ects, such as tardive dyskinesia, than typical neuroleptics. Studies of the distribution of the D4 receptor in the brain have shown that low levels of mRNA are present in the basal ganglia, in contrast to higher expression in the frontal cortex, medulla, amygdala, hypothalamus and mesencephalon (Van Tol et al., 1991; O'Malley et al., 1992). This `high' expression of the D4 receptor remains weak when compared with the expression of the other dopamine receptors. In fact, the relative

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abundance of the dopamine receptors in the rat central nervous system would be D1 > D2 > D3 > D5 > D4. Signi®cant levels of D4 mRNA are also found in heart (O'Malley et al., 1992), retina (Cohen et al., 1992) and the pituitary. Similar to the D3 receptor, the presence of the D4 receptor mRNA in limbic and cortical regions and its relatively low abundance in the striatum makes it an attractive target for novel antypsychotic drugs. The co-localization of D1 and D2 receptors within the same neuron is a topic that recently gave rise to controversial reports. By the use of in situ hybridization techniques with oligonucleotides and cRNA probes it has been clearly demonstrated that D1 and D2 receptor mRNAs are expressed in distinct neuronal populations, striatonigral substance P and striatopallidal enkephalin neurons, respectively, in the striatum (Le Moine and Bloch, 1995; Gerfen et al., 1990; Curran and Watson, 1995). These neuroanatomical ®ndings demonstrate that striatal neuropeptides have distinct dopamine receptor environments and strongly suggest that D1 and D2 receptors are segregated into distinct striatal output neurons. However, these ®ndings were challenged and other suggested that D1 and D2 receptors may in fact be partly or fully co-localized (Surmeier et al., 1992; Lester 1993). Recent investigation using immunohistochemistry procedure with D1 and D2 antibodies, mixed together on the same section with di€erent chromogens, did not show any co-localization and con®rmed, at the protein level, that D1 and D2 receptors are indeed segregated in distinct neurons of the dorsal striatum in an in vivo situation (Hersch et al., 1995). The same group that proposed that the D1, D2 and D3 receptors are completely colocalized in the same neurons in the striatum recently reported that this may not be completely the case (Carter-Russel et al., 1995). They proposed that the D1 and D2 synergism may be occurring by the co-expression in the same neurons of D1-like and D2-like receptors; i.e. the same neurons would express D1/D3/ D4 or D2/D5. The introduction of gene cloning procedures to the neurotransmitter receptor ®eld (Caron et al., 1990) resulted in a major shift in the understanding of the dopamine receptor system, and their previously unappreciated diversity was revealed. Bunzow et al. (1988) opened a new area in dopamine receptor research by cloning the ®rst dopamine receptor cDNA, that of the D2 receptor. It was demonstrated that dopamine receptors belong to the large G protein-coupled receptor family. Members of this family display considerable amino acid sequence conservation, especially in their seven transmembrane domains and on the basis of this homology, all ®ve of the dopamine receptor subtypes were cloned in a relatively short period of time (Gingrich and Caron, 1993; Jackson and Westlind-Danielson, 1994; Seeman and

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Van Tol, 1994). Although the existence of ®ve dopamine receptors had been previously unsuspected, the D1/D2 classi®cation concept developed in the late 70s is still relevant. The D1 and D5 receptors are classi®ed as `D1-like' because they share high sequence homology, stimulate AC and have the classical D1 pharmacology. The D2, D3 and D4 receptors are considered to be `D2-like', mainly because of their homology and pharmacology. The identi®cation of this multiplicity of dopamine receptors and their subsequent study has revealed a wealth of often unexpected information. Indeed, the identi®cation, isolation and sequencing of the genes and cDNAs for the ®ve dopamine receptors have provided information regarding their structure/ function relationships, their pharmacology and their precise distribution in the periphery and the central nervous system, giving valuable clues to their possible involvement and contribution to speci®c physiological functions. The amino acid sequence homology between the D1 and the D2 receptors is only 29% throughout the entire protein and 44% within the seven transmembrane domains. The chromosomal location of the human D1 gene is within the 5q35.1 locus (Grandy et al., 1991), a region containing several other cathecholamine receptor genes (Table 8) (Yang-Feng et al., 1990). Using the known homology between members of the G-protein coupled receptors family, another D1-like receptor was cloned in rat (D1b) (Tiberi et al., 1991) and human (D5) (Grandy et al., 1991; Sunahara et al., 1991; Weinshank et al., 1991). D1 and D5 share very high homology within their transmembrane domains, the region suspected to be directly involved in ligand recognition. It is therefore not surprising that these two receptors share a similar overall pharmacological pro®le (Table 8). Another interesting feature is the strikingly di€erent pattern of expression of these two receptors in the central nervous system. Indeed, D5 is expressed in brain areas previously unsuspected to contain dopamine receptors. As D1, and like many other catecholamine receptor genes, the D5 gene is intronless. It has been localized to the region 4p15.1±16.1, outside the Huntington's chorea gene locus (Table 8) (Gusella, 1989). Several pseudogenes for the human D5 receptor have been described that contain many inframe stop codons and appear to be transcribed but not translated. Similar to other G protein-coupled receptors, all of the dopamine receptors share a high degree of sequence homology within their transmembrane domains. Members of the same subfamily share considerable overall homology (78% for D1 and D5), although with a lesser degree for the D2-like subfamily (46% for D2 and D3; 53% for D2 and D4). Several conserved amino acids are found in the transmembrane domains of all the dopamine receptors and are

3.8 kb Fenoldopam SKF-23390 SKF-82526 SCH-23390 SCH-39166 (+)Butaclamol cis-Fluopenthixol Adenylyl cyclase (+) Phospholipid hydrolysis (+)

mRNA size Agonists (high anity)

Antagonists (high anity)

a

Legend: (+) stimulants, (ÿ) inhibitors.

Signal transduction

5q 35.1 No 446 (Rat) 446 (Human)

SCH-23390 SCH-39166 cis-Fluopenthixol (+)Butaclamol Adenylyl cyclase (+)

3.0 kb Fenoldopam SKF-38393 Dopamine

4p 15.1±16.1 No 457 (Rat) 477 (Human) Long 444 (Rat) 443 (Human)

Phospholipid hydrolysis (+) Arachidonic acid release K+ channels (+) Ca2+ channels (ÿ) Na+/H+ eschange (+) [3 HŠ thymidine uptake (+) Adenylyl cyclase (ÿ)

Spiperone Raclopride Sulpiride

11q 22-23 Yes Short 415 (Rat) 414 (Human) 2.5 kb Bromocriptine Dopamine Apomorphine

D2

D1 D5

D2-like

D1-like

Chromosomal localization Introns Amono acids

Receptor

[3 HŠ thymidine uptake (+) Na+/H+ exchange (+) Ca2+ channels (ÿ) Adenylyl cyclase (ÿ)

8.3 kb Quinpirole 7-OH-DPAT Apomorphine PD 128907 Spiperone Raclopride Sulpiride

3q 13.3 Yes 446 (Rat) 400 (Human)

D3

Table 8 Molecular biology and pharmacology of the dopamine receptors. The major characteric are presented (from Jaber et al. (1996) modi®ed)a

Spiperone Clozapine Sulpiride Olanzapine Arachidonic acid release (+) Adenylyl cyclase (ÿ)

5.3 kb Apomorphine Quinpirole Dopamine

11p 15.5 Yes 385 (Rat) 387 (Human)

D4

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thought to be implicated in dopamine binding. These include an aspartic acid residue in the third transmembrane domains and two serine residues in the ®fth transmembrane domains (Mansour et al., 1992; Tomic et al., 1993). The co-expression of various subtypes of dopamine receptors in the same brain region (such as the D1 and D2 in the striatum) and the inability to speci®cally target a dopamine receptor subtype by completely selective ligands makes it dicult to study the signal transduction associated with their activation in an intact tissue. The molecular cloning of the dopamine receptors has allowed the study of the properties of individual receptors in cultured cell lines. This has made it possible to examine the pharmacological speci®city of ligands for various receptor subtypes and also to begin to explore the modulation of second messenger pathways by these receptors. 5.3.1. D1-like receptors In all cell lines tested to date, the D1-like receptors stimulate the formation of cAMP in response to agonist (Gingrich and Caron, 1993; Jackson and Westlind-Danielson, 1994). In fact, some evidence indicates that the D5 receptor can constitutively activate adenylate cyclase, as well as cause a further increase in cAMP in response to agonist. In some cases, coupling of D1-like receptors to changes in intracellular Ca2+ concentrations has also been reported. In GH4C1 cells, the human D1 receptor stimulates adenylate cyclase and also increases the opening of L-type Ca2+ channels, possibly through the activation of protein kinase A (Demchyshyn et al., 1995; Sugamori et al., 1994). These discrepancies are likely to be due to the system in which the receptors are expressed. Despite the contradictory results concerning stimulation of phosphatidylinositol turnover in cultured cells, there is some evidence that in brain membranes a D1-like receptor stimulates phosphatidylinositol hydrolysis. D1 agonists stimulate the formation of inositol phosphate in both rat striatal slices and amygdala (Undie and Friedman, 1990), although the potency of dopamine to elicit this response is signi®cantly lower than for cAMP formation. In addition, recent evidence suggests that the D1 receptor may be capable of coupling to a PTX-sensitive G protein. Further work should clarify the second messenger pathways in addition to cAMP which the D1-like receptors in¯uence. 5.3.2. D2-like receptors Because of the clinical importance of the D2-like receptors (D2, D3 and D4) as potential targets for neuroleptic drugs and in some occasions for antidepressant drugs, much e€ort has been made to understand their signal transduction properties. D2 receptors were originally classi®ed as being coupled to inhibition

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of adenylate cyclase (Kebabian and Calne, 1979). Both the D2 short and long isoforms inhibit adenylate cyclase, although the D2 short isoform causes a greater maximal inhibition of cAMP and requires a lower dose of agonist to cause half-maximal inhibition than the D2 long isoform (Hayes et al., 1992; Montmayeur and Borrelli, 1991; Montmayeur et al., 1993). The D3 receptor has also been shown to inhibit adenylate cyclase (Chio et al., 1994b; McAllister et al., 1995), Inhibition of adenylate cyclase is evoked by the D4 receptor in mouse retina (Cohen et al., 1992), and CHO cells (Chio et al., 1994a). Like other receptors that couple to the inhibition of adenylate cyclase, the D2-like receptors are capable of modulating a variety of other second messenger pathways. Both D2 and D4 receptors have been shown to potentiate ATP- or calcium ionophore-evoked arachidonic acid release (Felder and Williams, 1991; Kanterman et al., 1991; Chio et al., 1994a). The D2-like receptors also mediate changes in intracellular Ca2+ levels via the inhibition of calcium currents. 5.4. g-aminobutyric acid An increase in the density of GABAB receptors is found for a series of antidepressants, including citalopram (Pilc and Lloyd, 1984). However, these results need to be con®rmed by other research groups, especially since another report found the density of GABAB receptor unaltered after 21 days of repeated treatment with either desipramine or zimelidine (Cross and Horton, 1987). The long-term studies have also demonstrated that there is no common denominator for receptor changes and that a functional change in certain receptor system is not predictive for antidepressant activity (Ciarcha et al., 1985). In contrast to these non-predictive tests, the suppression of rapid eye movement sleep is considered to be a predictor of antidepressant potential. In this test in cats TCAs, MAO-inhibitors and SSRIs are all active (Kovala et al., 1987; Scherschlicht et al., 1982). 6. Antidepressant drugs in the elderly The conventional drugs used in depression are: 1. tricyclic antidepressants (TCAs); 2. selective serotonin reuptake inhibitors (SSRI) and other new atypical antidepressants; 3. MAO inhibitors (IMAOs); 4. Mood stabilizing drugs, such as lithium, carbamazepine, phenytoin, valproate, verapamil, lamotrigine and gabapentin. In case of failure of these drugs and where a high risk

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of suicide exists, electroconvulsive therapy can be considered. In this review we are going to see those drugs having clinical implications in the elderly, pointing out especially the antidepressants which may be used with ecacy and are well tolerated. There is an old clinical adage that depressed patients who are starting to recover after the initiation of antidepressant treatment may ®nally get the energy to make and execute a suicide plan, so that clinicians must keep alert to the possibility of suicide even as the patient is improving. Thus, all of the antidepressants have a certain general risk of being associated with suicide, if not in a directly causative relationship. On the other hand, most of the data support the proposition that antidepressants reduce the suicide rate, not increase it, including ¯uoxetine. Nowadays, these drugs are also being used for the treatment of a variety of psychiatric disorders other than depression, including panic disorders, obsessivecompulsive disorders and bulimia nervosa and nonpsychiatric disorders, such as neuropathic pain, rheumatoid arthritis, osteoarthritis, etc. (Egberts et al., 1997). In the Rotterdam Study, a prospective study on 7812 individuals, the incidence of initiation of therapy with an antidepressant drug was approximately 1.3% per year and twice higher in women rather than in men. TCAs were the most used drugs, even if often at inadequate doses (Egberts et al., 1997). However, these data cannot be considered equivalent to the incidence of depression, just because two studies have indicated that only 70% of antidepressants are prescribed for treatment of depression (Isaccson et al., 1994; De Waal et al., 1996), moreover depression is often undertreated in the elderly (Eisenberg, 1992; Lecrubier, 1998) and antidepressant drugs are only one of the available modalities for treating this psychiatric disease (Egberts et al., 1997). Table 9 illustrates the of an `ideal' antidepressant administered to an elderly patient. 6.1. Tricyclic antidepressants The term `tricyclic antidepressant' is archaic by today's pharmacology. First, the antidepressants that block biogenic amine reuptake are not all tricyclic anymore: the new agents can have one, two, three, or four rings in their structures. Second, the tricyclic antidepressants are not merely antidepressant, since some of them have anti-obsessive compulsive disorder e€ects, others have antipanic e€ects. They are formed by three benzene rings, therefore they are called tricyclic and are the most commonly used drugs in depression therapy. In terms of the therapeutic actions of tricyclic antidepressants, they essentially work as negative allosteric modulators of

the neurotransmitter reuptake process. TCAs inhibit NA and 5-HT reuptake, but while biochemical block is already evident on the ®rst administration, the antidepressant e€ect is shown only after two or three weeks. However, the chronic administration of an antidepressant shows a b-adrenergic postsynaptic receptor desensitization and a decrease in receptor density for 5-HT; this evidence suggests that depression might be linked to a receptor supersensitivity, due to the increase of receptors and of their sensitivity and therefore antidepressants might act to promote a receptor down regulation (Garattini and Samanin, 1988; Sugrue, 1981). Besides, the hypothesis on the possible existence of speci®c receptors for tricyclic antidepressants is at present neither con®rmed nor excluded. When the neurotransmitters noradrenaline or serotonin bind to their own selective receptor transporter sites, TCAs are normally transported back into the presynaptic neuron. However, when certain antidepressants bind to an allosteric site close to the neurotransmitter transporter, this causes the neurotransmitter to be no longer able to bind there, thus blocking synaptic reuptake transport of the neurotransmitter. Therefore, noradrenaline and serotonin cannot be shuttled back into the presynaptic neuron. The classi®cation of tricyclic antidepressants may be made on the basis of chemical structure, or of the more or less speci®c action on some speci®c receptors or of clinical e€ects; it is shown in Tables 10±12. They are either tertiary or secondary amines; the secondary amines can be formed by oxidative N-demethylation of the corresponding tertiary amines (desipramine is derived from imipramine, nortriptyline from amitriptyline) (Sanders-Bush and Sulser, 1995). TCAs are rapidly absorbed from the gastrointestinal (GI) tract. Since they are lipophilic compounds and highly bound to plasma proteins (more than 90%) and to tissues; they have a long half-life and hence toxicity is increased in the elderly, being very dicult to remove these drugs by hemodialysis in case of overdosage. After an oral dose, a signi®cant portion has a ®rst pass metabolism through the liver; N-demethylation, aliphatic and aromatic hydroxylation represent the major metabolic pathways and the relative contriTable 9 The `ideal' antidepressant E€ective Pharmacologically selective Few or no side e€ects Few or no interactions with concomitant diseases No interactions with cytochromes Few or no interactions with other drugs administered in the elderly Safe in overdosage Simple administration (better if administered once daily) Fast onset of antidepressant activity

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bution of each varies from species to species (SandersBush and Sulser, 1995). In the elderly besides the major depression, TCAs are proven to be very ecacious in masked depression and in pseudodementia. Some of the tricyclics are also successfully employed for panic and obsessive compulsive disorders and chlorimipramine seems to be very e€ective in chronic pain (Sanders-Bush and Sulser, 1995). However, they have to be used carefully, as they may have dangerous side e€ects. Blockade of a1 adrenergic receptor causes orthostatic hypotension and dizziness. Anticholinergic actions at muscarinic cholinergic receptors cause dry mouth, blurred vision, urinary retention, and constipation. Blockade of H1 histamine receptors causes sedation and weight gain. But the most severe side e€ects are documented through some observations showing that by the late 70s, 1500±2000 individuals a year killed themselves in overdoses (Glassman and Bigger, 1981). Moreover, some studies suggested that they might cause arrhythmias and heart blocks (Je€erson, 1975) or they delay atrioventricular conduction and increase heart rate and on the electrocardiogram we can see prolonged PR, QRS and QT intervals, with non-speci®c T wave changes (Veith et al., 1982). Tricyclic drugs inhibit Na/ K ATPase dependent pump, which contributes to membrane stabilization, therefore they may cause arrythmias and heart arrest in patients with bundle branch block (Halper and Mann, 1988). Notwithstanding that, some antidepressants, such as for example imipramine, have an antiarrhythmic action, through a quinidine-like mechanism, a class Ia antiarrhythmic; but we know that every antiarrhythmic drug (especially quinidine, encainide, ¯ecainide and moricizine) may provoke severe arrhythmias, such as ventricular ®brillation up to heart arrest, especially under anoxic conditions, such as 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, es-

Table 10 The classi®cation of antidepressants according to their chemical structure Tertiary amines

Secondary amines

Imipramine Amitriptyline Chlorimipramine Dothiepin Trimipramine Doxepin Butriptyline Noxiptyline Desimipramine Nortriptyline Protriptyline

373

Table 11 Classi®cation of tricyclic antidepressants according to their speci®c action on speci®c receptors Reuptake inhibition of noradrenaline mainly Reuptake inhibition of serotonin mainly

Imipramine Nortriptyline Dothiepin Amitriptyline Chlorimipramine Desipramine

pecially in an old man with cardiac conduction disorders. The most common and important side e€ect of tricyclic antidepressants in an old man is orthostatic hypotension, which occurs with a still unknown mechanism (Allen, 1987). It seems to appear even at lowest dosages and to be related to the severity of depression, since it is less evident in normal individuals than in 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 e€ects 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-years old persons treated by tricyclics, this being just caused by orthostatic hypotension. Furthermore, these drugs may have important side e€ects on the central nervous system (CNS), in particular for their antimuscarinic e€ects. The anticholinergic e€ects are more marked for tertiary amines and may determine xerostomy, which may provoke moniliasis, parotitis, the rejection of dental prosthesis, malnutrition, with the following dangerous hydroelectrolitic disorders. Besides, they may provoke constipation, which at an extreme stage may cause a megacolon or a paralytic ileus and urinary retention for the lesser 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 Table 12 Classi®cation of tricyclic antidepressants according to their clinical e€ects Sedative-antianxiety action

Disinibition action

Amitriptyline Chlorimipramine Trimipramine Dothiepin Imipramine Desimipramine Nortriptyline

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characterized by anxiety, severe confusion, delirium and coma which require the immediate interruption of therapy in an old man, even if its appearance is unlikely at low dosages, like those used in the elderly (Jarvik et al., 1982). Recent memory de®cits, the lowering of epileptogenic threshold and a `tremor-dysarthria' syndrome are rather rare side e€ects (Table 13). Some of them may provoke sedation, i.e. all the compounds with an antihistaminic action, such as amitryptiline, or some troubles in falling asleep, i.e. those drugs with a disinhibiting action, such as nortriptyline. Now, let's see in more detail some of the most used tricyclic drugs. 6.1.1. Imipramine Imipramine was the ®rst 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 re-uptake. Even though its antimuscarinic e€ects are less marked than other tertiary amines, such as amitryptiline, it may provoke orthostatic hypotension and therefore it has to be used very carefully in the elderly. It also showed a lower hepatic clearance rate of imipramine in the elderly which then have a higher steady state plasma concentration (even if 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 altogether in the elderly. 6.1.2. Clomipramine It is a tricyclic which inhibits NA and 5-HT reuptake and determines b, a2 and 5-HT2 receptors downregulation. After oral administration, it is

absorbed in 2±3 h, undergoes hepatic metabolization to demethylclomipramine, which is pharmacologically active. Its plasma half-life is about 20±50 h and it is excreted by urine and faeces. The most important side e€ects are postural hypotension, anticholinergic e€ects, weight gain and sedation and cardiotoxic e€ects. Recent evidences suggest the possible onset of dependence (Toro et al., 1989). For all the above mentioned side e€ects, clomipramine is not a ®rst choice drug in the elderly. 6.1.3. Amitriptyline Amitriptyline is lipohilic like the other tricyclic antidepressants and is extensively bound; metabolism is predominantly to its pharmacologically active Ndemethylate metabolites, nortriptyline. It mainly determines the inhibition of 5-HT reuptake. Once it was used in the elderly for its sedative e€ects, but it is not certainly the main drug used in old people, since it has severe antimuscarinic and hypotensive e€ects (De Leo and Pavan, 1993). Furthermore, it has been frequently associated to central anticholinergic syndromes and conduction disturbances, therefore it has to be administered at low dosages. A clear e€ect of age on the pharmacokinetics of nortriptyline 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 and especially an interindividual variation (Nies et al., 1977). Some reviewers feel that this drug have no place in the treatment of depression in the elderly (Koenig, 1991), given the potentially severe adverse e€ects. 6.1.4. Doxepine Doxepine is a tertiary amine tricyclic with physicochemical properties similar to imipramine and amitriptyline, but with relatively low systemic availability (13± 45%) (Ereshefsky et al., 1988). It blocks mainly 5-HT reuptake. It is hepatically metabolized by demethylation to the metabolite demethyl-doxepin (el-Yazigi and

Table 13 The mean dosages, the plasma half-life and side e€ects of some tricyclics in the elderlya Drug

Imipramine Desipramine Chlorimipramine Trimipramine Amitriptyline Nortriptyline Doxepin Dothiepin a

Mean dosage/day (mg/die)

30±100 30±125 30±100 75±150 30±100 25±75 75±150 75±150

Plasma half-life (hours)

10±25 12±24 17±28 9±25 10±22 20±50 12±23 18±21

Side e€ects Sedation

Hypotension

Cardiac

Antimuscarinic

Seizures

+ + + + +++ + ++ ++

++ ++ ++ ++ ++ + ++ ++

++ ++ ++ ++ +++ + ++ ++

++ ++ ++ ++ +++ ++ +++ ++

+ + + + + + + +

One can note that nortriptyline appears as one of the best tolerated tricyclics in old people.

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Chaleby, 1988). It is excreted by the kidneys. The drug was recommended in a€ective disorders in the elderly, but it is contraindicated because of its antimuscarinic, sedative e€ects and some degree of orthostatic hypotension (Potter et al., 1991; Salzman, 1982). 6.1.5. Trimipramine It is a strongly sedative compound and it has severe anticholinergic e€ects comparable to amitriptyline and doxepine's ones. It mainly inhibits NA reuptake and, to a lesser extent, 5-HT reuptake. Chronic administration causes b, a2 and 5-HT2 serotoninergic receptor down regulation. It presents high anity for a-adrenergic and muscarinic receptors and an anity for histaminic receptors superior to amitriptyline. Peak plasma concentrations occurs 3 h after oral administration. Half-life is 22±24 h, it is biotransformed in a demethylated compound and undergoes renal excretion. Furthermore, it may be indicated in the patients with peptic ulcer, since it blocks H2 receptors (De Leo and Pavan, 1993). Secondary amines are more used than tertiary's in the elderly, because they have a simpler metabolism and less side e€ects, particularly desipramine, notriptyline, maprotiline and amoxapine. 6.1.6. Desipramine Desipramine is lipophilic and highly tissue and protein bound; its major metabolic pathway is via hepatic aromatic 2-hydroxylation to 2-hydroxydesipramine, a metabolite with probable both therapeutic and toxic activity that is excreted intact by the kidneys (Potter et al., 1979). It blocks NE reuptake, causes mild side e€ects if compared to imipramine or amitriptyline and so appearing as a potential choice in vulnerable populations such as old people, but its disinhibiting e€ects may cause insomnia. Some ®ndings 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-hydroxy-metabolite, but whether this may have clinical implications for therapeutic or toxic e€ects is not yet established. 6.1.7. Nortriptyline Nortriptyline is derived from demethylation of amitriptyline. It is a lipohilic and protein bound compound; its metabolism is primarily by hepatic oxidation to 10-hydroxy-nortriptyline, which may contribute to therapeutic and toxic e€ects. 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. Nortriptyline is well

375

absorbed, a plasma peak occurs 2±3 h after oral administartion and half-life is about 24±48 h. Its mechanism of action consists of the inhibition of NA reuptake and, to a lesser extent, of 5-HT. Chronic administration induces a b-receptor down-regulation. It presents a lower activity on a-adrenergic, histaminic and muscarinic receptors than amitriptyline and it is less sedative and antimuscarinic than tertiary amines. It has mild hypotensive e€ects; the therapeutic window, that is lower in the elderly than in the young, is about 50±140 ng/ml. Moreover, 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 into the elderly, probably due to a decrease in renal clearance. However, the link between concentration and any clinical e€ect remains uncertain. The most common side e€ects are dry mouth, sweating, constipation, asthenia, tachycardia, headache, somnolence and dizziness. 6.1.8. Dothiepin Its use in the old patient is controversial, because of the frequent side e€ects, such as tachycardia and orthostatic hypotension (De Leo and Pavan, 1993). It is a tricyclic antidepressant which is structurally similar to amitriptyline. The peak plasma concentration occurs at 3 h; elimination half-life is about 25 h and it is di€erent for males and females (Maguire et al., 1983). Dothiepin has two major metabolites, northiaden and dothiepin-S-oxide and it is excreted by kidneys. 6.1.9. Maprotiline It is tetracyclic, even though it is classi®ed among secondary amines, with less side e€ects than nortriptyline. It is largely used in the elderly population, but high dosages have to be forbidden, for the possible appearances of seizures. It selectively inhibits NA reuptake and has a high anity for histaminic receptors. Chronic administration determines b-noradrenergic receptor down-regulation. It has a modest activity on a-adrenergic and muscarinic receptors. It is fully absorbed after oral administration, it has a half-life between 30 and 50 h and is 88% protein bound. In the liver maprotiline undergoes demethylation, deamination and hydroxylation, resulting in the formation of methoxyderivatives. It is renally excreted and in part it has a biliary excretion. Steady-state occurs after 15 days. Its most common side e€ects are drowsiness, somnolence, blurred vision, constipation, sweating, headache, arrhythmias and memory impairment (Torta, 1999). 6.1.10. Amoxapine Amoxapine is a tricyclic antidepressant which is chemically derived from the neuroleptic loxapine, but

376

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appears to block selectively the neuronal reuptake of noradrenaline; it is qualitatively similar to desipramine. In studies of patients with mixed depressive illnesses it showed to be at least as e€ective as amitriptyline and imipramine in improving depressive symptoms (Dugas and Weber, 1982). It is metabolized to 8-hydroxyamoxapine and 7-hydroxyamoxapine; maximum levels occurs between 1 and 2 h after administartion, while mean elimination half-life is 9.8 2 2.6 h (Calvo et al., 1985). It is not used in the elderly because of its possible impairment of dopaminergic neurotransmission which causes extrapyramidal symptoms. Table 13 sums up the main characteristics of these drugs, including mean dosage and side e€ects. 6.2. Atypical antidepressants Recently, apart from tricyclic antidepressants, new molecules with the e€ects of tricyclics, but far less side e€ects were produced. Among these, ¯uoxetine, ¯uvoxamine, paroxetine, tianeptine, nefazodone, sertraline, citalopram, which are serotonin reuptake inhibitors (SSRIs), venlafaxine, which blocks serotonin and noradrenaline reuptake serotonin noradrenalene reuptake inhibitors (SNRI), viloxazine, which blocks noradrenaline reuptake, amineptine, amisulpride, which block dopamine reuptake, trazodone, lofepramine, mianserin, S-adenosyl-methionine, alprazolam, mirtazapine, reboxetine, a selective noradrenaline reuptake inhibitor (NARI) and L-tryptophane which act with di€erent mechanisms of action. There is a wide interindividual variability between the SSRIs with regard to their metabolism, pharmacogenetics and pharmacokinetics in elderly patients (Baumann, 1998); they seem remarkably less likely to be life threatening, even when ingested in dramatic overdoses (Table 14) (Glassmann, 1997, 1998). Since they were introduced, there are two documented deaths; one case was with ¯uoxetine (Kincaid et al., 1990) and the other with citalopram (Ostrom et al., 1996), but in both cases the patient ingested the equivalent to a six months supply at the usual dose of 20 mg daily. However, most of the cases where SSRIs were associated with mortality involved the co-ingestion of either alcohol or benzodiazepines (Glassmann, 1998). There is little evidence for cardiovascular toxicity, even in overdose, except that for tachycardia and occasional QRS widening (Glassmann, 1998). Other studies showed a modest slowing of pulse rate, but no in¯uence on either resting or postural blood pressure and on PR, QRS or QTc measures (Fisch, 1985; Fisch and Knoebel, 1992; Warrington et al., 1989). A case of severe sinus bradycardia was once reported (Ellison et al., 1990), while there were rare reports of supraventricular tachycardia, especially with ¯uoxetine (Gardner et al., 1991). Moreover, even in massive overdoses,

SSRIs have not been associated with arrhythmia; the most unexpected and potentially important observation to date about the SSRIs in patients with comorbid cardiac disease would be their putative anti-platelet activity (Glassmann, 1998). This means a bene®cial e€ect in post-infarction patients and other thrombotic diseases and theoretically a risk in discontinuating an SSRI in these patients. In overdose, the most common problem is seizures. At therapeutic doses, the most troublesome adverse e€ects are gastrointestinal, particularly anorexia and nausea, sometimes with associated vomiting, especially in individuals over 60 years of age, where a signi®cant bodyweight loss was observed in ¯uoxetine-treated patients (Brymer and Winograd, 1992; McManis and Talley, 1997). These adverse e€ects seem to be mediated by activation of 5HT3 receptors, either in the CNS or in the gastrointestinal tract, since they can be blocked by 5-HT3 antagonists such as ondansentron and cisapride, which is also a potent 5-HT4 agonist. Recent studies of SSRIs in experimental animals suggest how the neurotransmitter hypothesis of antidepressant action can be ampli®ed. That is, emphasis has moved from events occurring at the axon terminal to the somatodendritic autoreceptors near the cell body. In the depressed state, postsynaptic receptors may be up-regulated, and 5-HT may be de®cient not only at the axon terminal area but also at somatodendritic autoreceptors. When an SSRI is given acutely, 5HT rises due to blockade of the 5-HT transport pump. However, this occurs at ®rst only at the cell body area in the midbrain raphe, and not in the areas of the brain when the axons terminate. The e€ect of maintaining this increased 5-HT at somatodendritic autoreceptors is to down-regulate and desensitize them. Once the autoreceptors are down-regulated, 5-HT no longer regulates its own release, resulting in a ¯urry of 5-HT release from its axons and an increase in neuronal impulse ¯ow. There is a delay in how soon the increased somatodendritic 5-HT due to blockade of the 5-HT transport pump can down-regulate the somatodendritic autoreceptors in order to allow the neuron to be able to increase its 5-HT in axonal terminals and to increase its neuronal impulses. The delay in 5-HT arriving at the axon terminals may account not only for a delay in the down regulation of postsynaptic 5HT2 receptors but also for a delay in the therapeutic consequences of SSRIs. This theory thus suggests the pharmacological cascading mechanism whereby the SSRIs exert their therapeutic actions: it is hypothetically due to the restoration of neuronal impulse trac in the 5-HT neurons causing an increase in 5-HT release in axon terminal synapses with perhaps consequential postsynaptic 5-HT2 receptor down regulation. Therefore, if the ultimate increase in 5-HT at axonal synapses is critical, then its failure to occur may

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377

by symptoms and signs resulting from an increase of 5-HT in the CNS. The most frequent symptoms are myoclonia, diarrhoea, confusion, psychomotor agitation, hyperre¯exia, shivers, motor incoordination, fever, tremors, nausea, vomiting and blood pressure alterations. It is usually due to the administration of high doses of serotoninergic drugs, for example for the combination of an SSRI with a MAO-inhibitor or chlorimipramine (Zanardi et al., 1999). After giving up the active treatment, this syndrome disappears in 24 h. Cyproheptadine, a serotoninergic antagonist, proved to be very e€ective together with danthrolene, a muscle relaxant. Furthermore, the interaction between ¯uoxetine and MAOIs can lead to hypothermia, confusion and sometimes death, so that a 5 weeks wash-out is recommended between the interruption of therapy with ¯uoxetine and the beginning of an IMAO (Feighner et al., 1990). Moreover, in the elderly ¯uoxetine can determine the worsening of an atrial ®brillation or a synusal bradycardia (Bu€ et al., 1991). Surprisingly, it was shown that in patients with impaired cardiac contractility at baseline, ejection fraction improved signi®cantly after ¯uoxetine administration; this ®nding needs to be better investigated (Roose et al., 1998). Fluoxetine is associated with fewer antimuscarinic, cardiovascular and CNS adverse events, but greater number of gastrointestinal adverse events than those reported for the tricyclic antidepressants (Harris and Ben®eld, 1995; Feighner and Cohn, 1985). It often determines insomnia, nausea and vomiting. High serum concentrations of ¯uoxetine were described to probably cause widespread cognitive disorders, such as hyperkinetic delirium (Leinonen et al., 1993), but this needs to be further con®rmed. One should be careful

explain why some patients respond to an SSRI and some do not. Also, if new drugs could be designed to increase 5-HT at the right place at a faster rate, it could result in a much needed rapid acting antidepressants. Such ideas are only research hypotheses at this time, but could lead to additional studies clarifying the molecular events that are key mediators of depressive illness as well as of antidepressant treatment responses. 6.2.1. Fluoxetine Fluoxetine is a selective serotonin reuptake inhibitor (SSRI), which has a bicyclic structure. It is well absorbed after oral intake, is highly protein bound and has a large volume of distribution; it undergoes hepatic biotranformation to metabolites that include the Ndemethylation product nor¯uoxetine, pharmacologically active. Both parent drugs are characterized by long t1/2 values (1±3 days for ¯uoxetine and 7±15 days for nor¯uoxetine) and therefore ¯uoxetine is administered once daily; its clinical e€ects are very slow, but it is as e€ective as tricyclic antidepressants, even though it is structurally unrelated and is one of the ®rst line drugs in the elderly. Fluoxetine has a nonlinear pharmacokinetic pro®le, therefore it must be used with caution in patients with hepatic dysfunction (Altamura et al., 1994), but there are minimal age-related pharmacokinetics changes (Lemberger et al., 1985). Fluoxetine interacts with some other drugs, in fact it is an enzymatic inhibitor and therefore increase the blood concentrations of both antidepressants and antipsychotics. The interactions with lithium, triptophan and MAOIs are potentially serious and can lead to the `serotoninergic syndrome' (Altamura et al., 1994; Zanardi et al., 1999). It is a rare and severe syndrome characterized

Table 14 The mean dosages, the plasma half-life and side e€ects of some atypical antidepressants in the elderlya Drug

Trazodone Fluoxetine Fluvoxamine Citalopram Sertraline Paroxetine Minaprine Viloxazine Venlafaxine Amineptine Sulpiride Mianserin Reboxetine Mirtazapine

Mean dosage/day (mg/die)

75±300 20±40 100±200 20±40 50±200 20 150±200 150±300 75±375 100±200 25±50 40±80 4±8 15±45

Plasma half-life

6±8 48±68 15±20 36 24±36 24 2±20 2±6 5±7 24±48 15±30 6±30 12±14 20±22

Side e€ects Sedation

Hypotension

Cardiac

Anticholinergic

Seizures

++ ± ± + + ± ± + ++ ± + ++ ± +

+ ± ± ± ± + ± ± ± + + + ±

± ± ± ± ± ± ± ± ± ± ± ± ± ±

+ ± ± ± ± ± ± + ± + + ± ± ±

± ± ± ± ± ± ± ± ± ± ± ± ± +

a One can note that these drugs are much better tolerated than tricyclics, even if they are mostly proven to be very ecacious, so that they are the ®rst choice antidepressants in the elderly.

378

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when prescribing ¯uoxetine in the elderly, notably when a diuretic is prescribed as well, because severe hyponatremia, possibly due to inappropriate antidiuretic hormone secretion, was shown in 14 cases in literature (Ten-Holt et al., 1994). 6.2.2. Fluvoxamine Fluvoxamine facilitates 5-HT neurotransmission via potent and selective inhibition of serotonin reuptake into presynaptic neurons. It is well absorbed following oral administration to healthy volunteers; mean elimination half-life is approximately 19 and 22 h after single and multiple doses respectively and is not signi®cantly increased in the elderly. It undergoes extensive hepatic metabolism to at least 11 metabolites of which none possess psychotropic activity. More than 90% of a dose is eliminated in the urine as metabolites, while 4% of it is eliminated in the urine as unchanged drug (Wilde et al., 1993). While renal impairment has no e€ect on the pharmacokinetics of ¯uvoxamine, half-life elimination was increased in patients with hepatic impairment (Palmer and Ben®eld, 1994). The single study of 98 patients administered with ¯uvoxamine showed an unimodal distribution suggesting that a subpopulation of individuals who metabolize ¯uvoxamine abnormally does not exist (Palmer and Ben®eld, 1994). Its ecacy appears to be comparable to that of imipramine, clomipramine, dothiepin, desipramine, amitriptyline, lofepramine, maprotiline, mianserin and meclobemide (Wilde et al., 1993). It is very similar to ¯uoxetine, including the once daily administration and has mild side e€ects, i.e. nausea and vomiting. It seems to be particularly bene®cial 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, panic disorders and in the elderly too (Wilde et al., 1993). In fact in a 6 week comparative, nonblind general practice study of more than 5600 patients with depression, the ecacy of ¯uvoxamine in patients aged 60 years or older (n = 1096) was similar to that in younger patients (Martin et al., 1987). In another large non-comparative study of patients with depression, the ecacy of ¯uvoxamine was also similar in elderly and younger patients (Stollmaier et al., 1989). 6.2.3. Paroxetine It has been introduced recently, is a phenyl-piperidinic derivative, with a strong and selective serotonin reuptake inhibition (5-HT2A). It has also little anity for a1-adrenergic, b-adrenergic, dopamine, histamine H1 and acethylcholine receptors (Nemero€, 1993). Its bioavailability is not a€ected by food or antiacids and its mean plasma half-life of about 24 h is consistent with once a day dosing. It undergoes a partially saturated ®rst 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 anity to the cytocrome P450, isoenzyme CYP2D6, indicates that interference occur 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 ecacy to ¯uoxetine in the treatment of elderly depressed patients, improving also all measures of cognitive and behavioural functions (Geretsegger et al., 1994). Paroxetine showed to be ecacious in preventing the relapse of depression during long term treatment, even if further research is required and has few side e€ects, such as nausea and other gastrointestinal disturbances, few antimuscarinic and CNS adverse e€ects, 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. In depressed patients paroxetine also showed to normalize platelet factor 4 and b-thromboglobulin, two proteins whose rise seems to increase the readiness of platelets to aggregate (Laghrissi-Thode et al., 1997; Pollock et al., 1995). 6.2.4. Sertraline Sertraline is a 5-HT reuptake inhibitor that has been approved for use in the treatment of depression in the elderly too. After prolonged treatment a 5-HT1 and 5HT facilitates 5-HT2 receptor down-regulation. Sertraline presents a low or no anity for histaminic, muscarinic and a-adrenergic receptors. Plasma peak concentrations occur 4±8 h after oral administration, with a half-life of 24±26 h. Its main metabolite is Ndemethyl-sertraline, pharmacologically active and a half-life longer than its precursor. It has a linear pharmacokinetics without any in¯uence of aging on its plasma levels. Steady-state usually occurs after a week. Its side e€ects pro®le is similar to ¯uoxetine. It is nonsedating, free of cardiac e€ects, does not cause orthostatic hypotension, urina retention or blurred vision. The only side e€ects involve the gastrointestinal tract. This makes sertraline a safe drug in depressed elderly patients too (Auster, 1993). A 5-HT reuptake inhibitory antidepressant recently experimented in elderly volunteers is medifoxamine (Gainsborough et al., 1994), even though the good results need to be con®rmed further. 6.2.5. Citalopram 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 a lipophilic compound, well absorbed after oral administration. Food does not in¯uence its bioavailability (Zanardi et al., 1999); plasma peak con-

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centration is reached after 2±4 h and its half-life is about 35 h. Steady-state concentrations are reached after 1±2 weeks of treatment. Citalopram and its metabolites are approximately 80% protein bound. Citalopram undergoes liver metabolism with demethylation, deamynation and N-oxydation; this leads to less lipophilic compounds rapidly excreted by urine, whilst up to 65% of oral dose undergoes a faecal excretion. Citalopram has minimal interactions with other drugs because it causes a low inhibition of CYP2D6, CYP3A4 and CYP1A2; on the contrary, phenotiazines may determine an increase in citalopram concentrations (Zanardi et al., 1999). Although demethylation of citalopram attenuates the e€ects on 5-HT and to a lesser extent, NA uptake, demethylcitalopram and didemethylcitalopram are still selective 5HT uptake inhibitors in vitro with IC50 NA/IC50 5-HT ratios of 53 and 64, respectively (Hyttel, 1994). This antidepressant is also as e€ective therapeutically as the old antidepressants, but it produces considerably fewer e€ects than amitriptyline. Citalopram appears to have minimal e€ects on the cardiovascular system and is one of the few antidepressants to be eliminated by the kidneys. Its ecacy together with its good tolerability cause it to be particularly recommended in elderly depressed patients, even with more or less severe organic diseases. 6.2.6. Tianeptine Tianeptine is a novel antidepressant agent, both structurally, (it is a modi®ed tricyclic) and in terms of its pharmacodynamic pro®le. It stimulates the uptake of 5-HT in rat brain synaptosomes and rat and human platelets and increases 5-hydroxyindoloacetic acid (5HIAA) levels in cerebral tissue and plasma and reduces serotoninergic-induced behaviour (Wilde and Ben®eld, 1995). Tianeptine reduces the hypothalamicpituitary-adrenal response to stress and it showed its ecacy in major depression, depressed bipolar disorder with or without melancholia and in dystymic disorder. It is also e€ective in the treatment of depression in the elderly and post-alcohol-withdrawal patient subgroups (Wilde and Ben®eld, 1995). In fact, animal studies have shown that alcohol consumption is reduced when serotonin levels are increased in the CNS (Lejoyeux, 1996). Multiple dosing of tianeptine after oral administration are well tolerated (Demotes-Mainard et al., 1991). Tianeptine and its MC5 metabolite (C5 acid analogue of tianeptine) reach maximum plasma levels after 1.8 2 0.99 and 2.96 2 1.44 h respectively. Tianeptine kinetics is linear and this is similar in elderly and the young. It is eliminated from plasma with a half-life of 2.521.1 h, mainly via extrarenal route (Salvadori et al., 1990). Its antidepressant anxiolytic properties appear to be

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similar to amitriptyline, imipramine and ¯uoxetine and even superior to maprotiline. Tianeptine showed to be well tolerated in the short and long term therapy (up to one year). Dry mouth, constipation, dizziness, syncope, drowsiness and postural hypotension are less frequent with tianeptine than with tricyclics, such as amitriptyline, whilst insomnia and nightmares occur more frequently (Wilde and Ben®eld, 1995). Given the relative lack of sedative, anticholinergic and cardiovascular adverse e€ects, it is particularly suitable in the elderly. 6.2.7. Nefazodone It is a new serotoninergic antidepressant, with an ecacy in elderly patients comparable to imipramine, which reported few side e€ects, such as dose-related impairment of cognitive and memory functions. However its action still needs to be better investigated (Van Laar et al., 1995). It makes part to a new class of antidepressants known as phenylpiperazines, which blocks 5-HT2 receptors and includes nefazodone and trazodone. The pharmacological mechanism of action derives from the combination of a powerful antagonism of 5-HT2 receptors with a weaker blockade of 5-HT reuptake; these agents are classi®ed separately as serotonin antagonists reuptake inhibitors (SARIs) (Stahl, 1996). The major distinction between the SARIs and other classes of antidepressants is that SARIs are predominantly 5-HT2 antagonists, yet combine a lesser amount of 5-HT reuptake inhibition. When 5-HT reuptake is inhibited selectively, as with the SSRIs, it causes essentially all serotonin receptors to be stimulated by the increased levels of 5-HT that result. Although this has proven to be quite useful for treating depression and other disorders, this also has its cost. For example, stimulation of 5-HT1A receptors in the raphe may help depression, but simulating 5-HT2 receptors in the forebrain may cause agitation or anxiety, and stimulating 5-HT2 receptors in the spinal cord may lead to sexual dysfunction. Thus, an agent that combines 5-HT reuptake blockade with stronger 5-HT2 antagonism would theoretically reduce the undesired actions of 5HT stimulating 5-HT2 receptors. In this case, competition between weak reuptake blockade and strong 5HT2 antagonism results in net antagonism at the 5HT2 receptor. The SARIs in fact appear to lack the activating properties of some of the SSRIs, such as agitation, anxiety and akathisia and also lack the sexual dysfunction associated with the SSRIs. Nefazodone appears to lack the strong sedating, antihistaminic, and in vivo a1-adrenoceptor antagonist properties of trazodone, to which it is chemically related. The elimination of unwanted antihistaminic activity could explain the enhanced tolerability (especially improved sedation) of nefazodone over trazodone. Another

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di€erence between trazodone and nefazodone is that there are only very weak a1 antagonist properties of nefazodone in vivo, even though it antagonizes binding at a1 receptors in vitro. The di€erences may be that nefazodone also has the ability to inhibit noradrenaline uptake, which trazodone lacks. Thus, at the NA synapse, relatively equal amounts of a2 blockade on NA reuptake blockade causes increased synaptic NA that competes with nefazodone for the a2 receptor, and o€sets its actions there. However, with trazodone, there is no NA reuptake blockade to o€set a-receptor antagonism and thus a-antagonist properties predominate for trazodone. This di€erence may account for the reduced incidence of orthostatic hypotension and so far as of this writing, no cases of priapism with nefazodone compared to trazodone have been reported. Improving the side-e€ect pro®le of trazodone by eliminating unwanted receptor blocking properties is a strategy comparable to enhancing the tolerability of the SSRIs over the TCAs once the histamine, muscarinic, and a-adrenergic properties of the TCAs were removed. Whether nefazodone will prove to have novel ecacy due to its novel predominant 5-HT2 antagonist properties is yet to be known (Stahl, 1996). Nefazodone is completely and rapidly absorbed after oral administration with a peak plasma concentration 2 h after administration (Greene and Barbhaiya, 1997). It undergoes signi®cant ®rst-pass metabolism resulting in an oral bioavailability of approximately 20%; it can also be administered without any regard to meals. Nefazodone has three major metabolites, hydroxynefazodone, trizoledione and m-chlorophenylpiperazine (mCPP); its pharmacokinetics is non-linear. A steady-state occurs after 4 days from the beginning of the administration (Greene and Barbhaiya, 1997). The pharmacokinetics is altered in severe hepatic impairment and in elderly females; in fact it is a weak inhibitor of CYP2D6, whilst does not inhibit CYP1A2 and it is metabolised by and inhibits CYP3A4 and this arises a number of questions about interactions with other drugs, such as carbamazepine, triazolam and alprazolam, cyclosporin (Greene and Barbhaiya, 1997). 6.2.8. Trazodone Trazodone has a di€erent chemical structure from the other antidepressants, in fact it is a triazolopyridine derivative biotransformed principally to the active metabolite metachlorophenylpiperazine (mCPP) by hepatic microsomial oxidation. It determines an increased NE release and turnover, by acting on a2presynaptic receptor and has an ecacious antidepressant action in old people and a moderate anxiolytic and hypnotic activity (Haria et al., 1994). It is a 5-HT2 antagonist and as already shown for its correlated drug, nefazodone, an in vitro 5-HT reuptake inhibition was also shown (Beasley et al., 1991). It has a

short half-life, so that it requires multiple administrations, this being a partial disadvantage, especially in elderly persons with a polypharmacotherapy. The most common side e€ects are dizziness, drowsiness and especially orthostatic hypotension, while there are no antimuscarinic e€ects, except xerostomy. Priapism, heart arrhythmias were also observed in few cases; besides, since it may cause gastric irritation, its administration after meals is appropriate. In terms of therapeutic ecacy, trazodone appears to confer little advantage over other available antidepressants, such as amitriptyline, imipramine, ¯uoxetine and mianserin; it may be a drug of ®rst choice in elderly patients in whom anxiety and insomnia are problematic 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 (Greenblatt et al., 1987). A need for reduced dosage can be anticipated for the elderly, although a relationship between steady state serum concentration and clinical e€ects is not established. Studies are also required to establish its place in long term pro®lactic therapy for recurrent depression. 6.2.9. Minaprine It has an original chemical structure and not only seems to be able of increasing the intracerebral levels of serotonin but also activates dopaminergic neurotransmission. It inhibits the reuptake of dopamine and it is also a weak reuptake inhibitor of 5-HT and NE. The compound is quickly adsorbed following oral intake, is highly protein bound and shows a hepatic metabolism with several active metabolites. The halflife is of 6±13 h (Torta, 1999). Minaprine appears to have the same ecacy of imipramine, but less side e€ects. The only side e€ects are insomnia and restlessness and especially it has no cardiovascular side e€ects, therefore is a drug of common use in the elderly. 6.2.10. 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 e€ects associated with activity at other receptors (Bolden-Watson and Richelson, 1993), especially in the long-term treatment of depression (Shrivastava et al., 1994) and an enhanced response with increasing doses (Rudolph et al., 1991). Animal models show that contrary to tricyclics, venlafaxine and its metabolite may reduce b-adrenergic sensitivity both after acute and chronic administration; this means a more rapid beginning of activity for the atypical antidepressant. After an oral dose, its peak plasmatic con-

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centration occurs in about 3 h, whilst it occurs in 6 h for tablets at extended release at present available. Plasma half life is approximately 5 h, 15 h for tablets at extended release. Its main metabolite is oxydemethyl-venlafaxine; they have a low protein binding (27% and 30% respectively) and are excreted by kidneys (Troy et al., 1997). Venlafaxine is a weak inhibitor of CYP2D6, while it does not inhibit CYP1A2, CYP2C9 and CYP3A4. In a randomized, double-blind ®xed-dose comparison of placebo and three doses of venlafaxine (75, 225 and 375 mg), the drug was more e€ective 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., 1992; Schweitzer et al., 1994) and superior to ¯uoxetine (Clerc et al., 1994). The most common reported adverse drug e€ects associated to venlafaxine were nausea, somnolence, sweating and dizziness. Pulse rates and blood pressure increased slightly, while weight decreased. Therefore, it is safe in elderly patients, even for treatment of major depression and in prolonged treatments. A careful administration is always required in patients with a recent history of myocardial infarction. 6.2.11. Viloxazine It has a bicyclic structure and is an antidepressant which selectively inhibits NA reuptake; it has an antihistaminic and a weak anticholinrgic activity. Viloxazine is rapidly absorbed with a plasma peak concentration 2 h after oral administration and a plasma half-life between 5 and 10 h (Torta, 1999). It has no active metabolites and has to be carefully administered in the patients with heart disease. Headache and nausea (of central origin) are the main side e€ects. 6.2.12. Amineptine It is a tricyclic compound, even though it di€ers for the presence of a long chain which ends with an acid radical. Its psychostimulant e€ect is inferior to MAO inhibitors only. Amineptine inhibits DA reuptake and facilitates its release; it has no activities on adrenergic, cholinergic and histaminic receptors. Plasma peak concentration occurs 1 h after oral administration; plasma half-life includes a rapid phase of 2 h and a slow phase of 24 h. At high dosages skin reactions may be observed, sometimes severe acne-like lesions; at the beginning of the treatment palpitations, irritability, insomnia and lowering of blood pressure occur. Nausea, jaundice, muscular and articular pains, and fever of unknown origin may be seldom present. Anxiety was observed in the ®rst two weeks of treatment and rarely, cholestatic hepatitis. However, it was dismissed

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from commerce since last April 1999, since some data showed a consistent risk for dependence (Bertschy et al., 1990; Duriot et al., 1991). 6.2.13. Nomifensine Nomifensine is a potent inhibitor of NA but has little e€ect on 5-HT too and it is a potent reuptake inhibitor of DA. Nomifensine is rapidly and completely absorbed and is widely distributed throughout the body; its major route of elimination is through the kidneys (Kinney, 1985). It has a short half-life and has been found to be as e€ective as the standard antidepressant agents. It is safe and e€ective and causes little sedation, together with minimal anticholinergic side e€ects, no impairment of psychomotor performance and a relative lack of cardiotoxicity and epileptogenic activity; therefore, it can be used in the elderly (Fields, 1982). 6.2.14. Sulpiride and amisulpride This recently introduced drug belongs to 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 e€ects which are characteristic of this class of drugs, i.e. precocious dyskinesia (sti€ neck, oculogir crises, trismus), extrapiramidal syndrome, requiring an antiparkinsonian treatment, tardy dyskinesia, observed in the case of prolonged treatments and some endocrine e€ects, such as hyperprolactinemia, galactorrhea, gynecomastia, etc. It may also potentiate the e€ects of antihypertensive, hypnotic and analgesic drugs. Amisulpride, also belonging to the category of substituted benzamides, selectively acts on dopaminergic transmission with a bifasic pharmacodynamic pro®le. In fact, at low doses it is a dopamine agonist, whilst at high doses it is a dopamine antagonist and therefore it has an antipsychotic activity. Amisulpride presents a rapid absorption, peak plasma concentration occurs in 1±5 h. Plasma half-life is biphasic, with a fast phase of 2±5 h and a slow phase between 15 and 18 h. Steadystate occurs in 48±72 h. Amisulpride presents a hepatic metabolism which leads to unactive compounds and it is excreted by kidneys, mostly as an unmodi®ed compound (Torta, 1999). Its side e€ects include sedation, somnolence, early and late diskynesia, extrapiramidal syndrome, impotence, hyperprolactinemia, weight increase, galactorrhea, ginecomasty, dysmenorrhea, dyspnea, muscular pains, etc. It was also shown to be e€ective in dysthymia and in the so-called `subsyndromal' manifestations of depression, enclosing the `prodromal' or the `residual' forms of major depression (Delle Chiaie and Caliari, 1997). 6.2.15. Lofepramine It is a tricyclic antidepressant that di€ers from imi-

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pramine for the presence of a lipophilic compound, but has less side e€ects and it is metabolised to desipramine. Its antidepressant activity seems to derive from the facilitation of noradrenergic neurotransmission by uptake inhibition and by the additional facilitation of serotoninergic neurotransmission (Lancaster and Gonzalez, 1989). Its pharmacokinetics in the elderly is comparable to the young (Ghose and Spragg, 1989). Peak plasma concentrations is reached at about 1 h and elimination half-life is 2.5 h. A 24fold interindividual variation in peak plasma concentrations was observed (Ghose and Spragg, 1989). The overall therapeutic ecacy is comparable to amitriptyline, clomipramine, maprotiline and mianserin in patients with depression associated to anxiety. Dry mouth is the most commonly reported side e€ect and it has not been associated with adverse e€ects on cardiac function even in attempts of suicide by overdose. Case reports of hepatic toxicity caused clinicians to question its use in patient population 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 ®rst 12 weeks of treatment is recommended. 6.2.16. Mianserin It is a tetracyclic compound which seems to have only a mild e€ect on the reuptake of monoamines; it increases intrasynaptic adrenaline by determining a down-regulation of presynaptic a2-adrenergic receptors and presents a powerful antihistaminergic and a weak anticholinergic activity. Mianserin is rapidly absorbed, plasma peak concentration occurs 2±3 h following oral administration, with a remarkable ®rst-pass hepatic metabolism and a plasma half-life between 10 and 40 h (Torta, 1999). Its main side e€ects are hypotension, seizures, articular pains, increase of transaminases. A careful evaluation of the right dosages must be set in the elderly patients. It is mostly indicated 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 e€ects in the elderly. Mianserin causes marked sedation, mild orthostatic hypotension and has no antimuscarinic e€ects. 6.2.17. Alprazolam Even belonging to benzodiazepines, alprazolam is proven to be a good and safe antidepressant drug, especially in those forms of depression associated to

anxiety and it is a GABA-agonist facilitating inhibitory action of GABA on the CNS. Alprazolam is rapidly absorbed after oral administartion, with a plasma peak concentration in 2 h. Plasma half-life is about 10±15 h; it has an active hydroxylated metabolite (Torta, 1999). It may be administered to elderly patients too, even though to mild dosages; it has not to be used if a narrow-angle glaucoma, severe airway diseases, hepatic failure and miasthenia are present. 6.2.18. Reboxetine Reboxetine is the ®rst drug of a new class of antidepressants, called noradrenaline reuptake inhibitor (NARI); it has no interactions with other drugs thanks to the lack of inhibition of cytochrome P450 and it has no anity for adrenergic, muscarinic and histaminergic receptors. Its bioavailability is 80%, the volume of distribution is 32 l and the a1-glicoprotein binding is 37%. The half-life was estimated to be 13 h. Nausea, dyarrhea, somnolence, hypotension, constipation and dry mouth are the most common observed side e€ects, even if they seem to be more frequent than those related to the use of tryciclic antidepressants. Its use in the elderly need to be better investigated, since actually there are only few evidences. Previous data demonstrated that the clearance is markedly reduced in the elderly and during renal insuciency. Reboxetine showed to improve social adaptation better than ¯uoxetine, evaluated by Social Adaptation Self-evaluation Scale (SASS) (Bosc et al., 1997; Dubini et al., 1997). Short latency time before the onset of pharmacological e€ect and high tolerability are two great advantages of this compound. 6.2.19. S-adenosyl-methionine (SAM) It may be used in the elderly because it has practically no side e€ects. SAM increases NA and 5-HT turnover, stimulates phospholipid methylation, so that membrane synaptosome ¯uidity and b-adrenergic reactions are preserved. After i.v. administration, the drug presents a rapid distribution to tissues with an elimination half-life of approximatively 80 min; peak plasma concentration occurs 30 min after intramuscular administration. It is also well absorbed if administered orally and it has a renal excretion (15%) and through faeces (25%) (Torta, 1999). 6.2.20. L-tryptophan It is a 5-HT precursor and can potentiate tricyclic and MAO-inhibitors antidepressant action. It is converted to 5-HT in brain tissue. L-triptophan is well absorbed, crosses blood±brain barrier and presents a plasma half-life of about 6 h. It is excreted by kidneys as hydroxy-indol-acetic acid (HIAA) (Torta, 1999).

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6.2.21. Mirtazapine Mirtazapine is the ®rst of a new class of antidepressants, the NA and speci®c 5-HT antidepressants (NaSSA). Its e€ect appears to be linked to the enhancement of central NA and 5-HT1 receptormediated serotoninergic neurotransmission (Kasper et al., 1997). In fact, mirtazapine blocks presynaptic a2adrenergic receptors and post-synaptic 5-HT2 and 5HT3 receptors (Puzantian, 1998). It is well-absorbed, with a linear pharmacokinetics and an elimination half-life of 20±40 h, thus allowing once daily administration. This drug is extensively metabolized by the cytochrome-P450 system, therefore its clearance is reduced in hepatic or renal impairment. However, studies on extensive and poor metabolizers of debrisoquine have shown that strong inhibitors of CYP2D6 have no in¯uence on the concentrations of mirtazapine; conversely, mirtazapine may inhibit the metabolism of co-administered drugs metabolised by CYP1A2, CYP2D6 and CYP3A4. It is excreted by the kidneys. In comparative trials, patients receiving mirtazapine showed signi®cantly greater improvement as measured by scores on the Hamilton Rating Scale for Depression (HAM-D) and Montgomery-Asberg Depression Rating Scale scores compared with placebo. It showed to be equally e€ective as clomipramine, amitriptyline and doxepin, among tricyclic antidepressants and trazodone and ¯uoxetine, among atipycal antidepressants. Mirtazapine also showed to have some bene®cial e€ects on anxiety and sleep disturbances. It has demonstrated superior tolerability to tricyclics on account of the relative absence of anticholinergic e€ects; the most commonly reported adverse e€ects are somnolence, increased appetite, weight gain, dizziness and sexual dysfunction (Kasper et al., 1997; Puzantian, 1998). 6.2.22. Hypericum Hypericum perforatum extract (St. John's wort) appears to be a safe and e€ective alternative drug in the treatment of depression (Josey and Tackett, 1999). It was introduced into Australia during the 80s for medical purposes, but was subsequently declared a noxious weed (Rey and Walter, 1998). Recently it was shown to be e€ective in mild to moderate depression, this depending on its hyperforin content (Laakmann et al., 1998). Standardized solid extracts (0.3% hypericin) were favorably compared to several antidepressant drugs and studies have also demonstrated its ecacy in treating seasonal a€ective disorders (Martinez et al., 1994; Vorbach et al., 1994, 1997; Miller, 1998) and mild depression with somatic symptoms (Hubner et al., 1994). Moreover, in vitro investigations show antiviral activity, while traditional uses include enhancement of wound healing, anti-in¯ammatory and analgesic activity (Miller, 1998).

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Its clinical ecacy could be attributable to the combined action of a number of mechanisms, similar to those of the selective 5-HT reuptake inhibitors or monoamine-oxidase (MAO) inhibitors, even if other mechanisms are possible (Bennett et al., 1998). The fact that hypericum is a safe antidepressant suggests its use in the elderly. The most common adverse e€ects are gastrointestinal symptoms, dizziness, confusion, tiredness, excessive sedation and rarely photosensitivity (Ernst et al., 1998a). More studies are required to evaluate its use in severe depression. 6.2.23. Bupropion Bupropion is an e€ective antidepressant, generally activating or even stimulating but it is not a ®rst choice drug in the elderly, since it requires multiple administrations and has a low therapeutic index. It blocks DA reuptake. Bupropion is well absorbed if administered orally, undergoes hepatic metabolism and it has three major metabolites (hydroxybupropion and the aminoalcohol isomers threohydrobupropion and erythrohydrobupropion). Half-life is about 18 h and it is excreted by kidneys (Hsyu et al., 1997). Its main side e€ects are anxiety, insomnia and it can seldom induce seizures, so that the association with a sedative drug is required in epileptic patients. It has no cardiovascular, sedative, or anticholinergic e€ects (Morocutti et al., 1998), but it has triggered seizures in a small number of patients (0.4%) (Sanders-Bush and Sulser, 1995), in fact an increased incidence of grand mal seizures compared to other antidepressants, which also cause seizures, but in lesser frequency. A new controlled-release formulation of bupropion is a promising improvement that may reduce both the frequency of dosing to only once or twice a day as well as the side e€ects associated with peak plasma blood levels of the drug. Interestingly, bupropion does not appear to be associated with production of bothersome sexual dysfunction that can occur with the SSRIs, probably because it lacks a signi®cant serotonergic component to its mechanism of action. Thus, it may be a useful antidepressant not only for patients who cannot tolerate the serotonergic side e€ects of SSRIs but also for patients whose depression does not respond to serotoninergic boosting by SSRIs. It is prescribed predominantly in the United States and mostly by psychiatrists, whereas most other antidepressants are prescribed throughout the world and predominantly by nonpsychiatric practitioners who treat depression. Table 14 sums up the main characteristics of these drugs, including mean dosage and side e€ects. 6.3. Mao-inhibitors Drugs of this class inhibit mithocondrial monoamine oxidase (MAO) both in the CNS and in peripheral tis-

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sues. MAO are isoenzymes of two classes, A and B: the former mainly metabolize NA (Fig. 5) and 5-HT (Fig. 6), while the latter metabolize dopamine (Fig. 4). However, MAO-B inhibitors, like L-deprenyl, even though have less side e€ects, are not as potent as MAO-A inhibitors in the antidepressant action. The antidepressant ecacy of MAO-A may be referred to the increase in the intrasynaptic concentration of monoamines and to reduce the levels of the corresponding deaminates metabolites, e.g., they increase NE and lower 3-methoxy-4-hydroxymandelic acid (VMA) and 3-metoxy-4-hydroxyphenylglycol (MHPG) or they increase 5-HT abd reduce 5-hydroxyindole acetic acid (5-HIAA). Trace monoamines, such as tryptamine and octopamine, are also increased after MAO inhibition. Nevertheless, as seen for tricyclics, while enzymatic block is just evident after the ®rst administration, the clinical results need 15±20 days to appear. Therefore, it is at present thought that enzymatic block is only the ®rst step of a more complex mechanism (Hauger et al., 1988). Like the tricyclic antidepressant, MAO inhibitors produce a delayed down-regulation of b-adrenoceptors in brain and this ®nding has contributed to the revised catecholamine hypothesis of depression. Chronic administration of MAO-inhibitors to rats also elicits a delayed down-regulation of 5-HT1 and 5-HT2 receptors in brain. In addition, the behavioural and electrophysiological e€ects of 5-HT agonists are attenuated by chronic MAO inhibition, presumably mediated by down- regulation of receptors. MAO inhibitors are rapidly absorbed after oral administration; N-acetylation is a major route of metabolism of hydrazines, such as phenelzine and isoniazid. Studies of the metabolism of hydrazines suggest that patients with fast or slow acetylation of these drugs di€er in therapeutic response and toxic reactions. Isocarboxazid is metabolized by cleabage to benzylhydrazine, with ultimate secretion in the urine as hippuric

Fig. 4. Schematic representation of antidepressant drugs acting on dopaminergic neurotransmission.

Fig. 5. MAO-A metabolize noradrenaline into an aldheide, from which derive dihydroxy-mandelic acid (DHMA) and dihydroxyphenylglycol (DHPG). Catechol-O-methyltransferase (COMT) metabolize these compounds into vanil-mandelic acid (VMA) and methossyhydroxyphenylglycol (MHPG) respectively.

acid; hippuric acid is also a major urinary metabolite of tranylcypromine. The duration of action of these drugs is determined by enzyme regeneration of MAO, rather than drug inactivation. MAOIs are indicated in the forms of depression refractory to TCAs, in panic attack disturbances, in dementia-associated depression (non severe forms), in atypical depression (West and Dally, 1959) and in social phobia (Fyer and Gorman, 1986). They have mild antimuscarinic e€ects; it is very unusual for a patient treated with this drug to complain of xerostomy, sweating, accomodation disturbances and 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 occurs for the interactions with food containing tyramine, tryptophan and tyrosine, such as cheese, alcohol (in particular red wine), seasoned food, bananas, beans, dry fruit, pineapple, acid creams, etc. (`cheese e€ect'). In fact, tyramine contained in food is usually metabolized by intestinal and hepatic MAO. If they are inhibited by a MAOI, tyramine goes into bloodstream and may cause hypertensive crises. However, this might occur only with the oldest MAOIs, characterized by an irreversible link to MAO, such as phenelzine, isocarboxazide and tranylcipromine (Table 15). This means that they are not suitable in elderly patients. Nevertheless, recent research resulted in the

Fig. 6. MAO-A metabolize 5-hydroxytriptamine into 5-hydroxyindolacetic acid (5-HIAA).

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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 far less side e€ects than TCAs and classical MAOIs. Acute overdose with MAOI causes agitation, hallucinations, hyperpyrexia, hyperre¯exia and convulsions. Abnormal blood pressure is also a toxic sign, so that gastric lavage and maintainance of cardiopulmonary function may be required. 6.3.1. RIMAs RIMAs include meclobemide, broforamine, toloxatone and cimoxatone, of which meclobemide is the most studied and it is also used in the treatment of depression in elderly people. Meclobemide is a derivative of benzamide which inhibits MAO-A rapidly, selectively and reversibly. Recovery of MAO-A activity occurs within 16 h (Kan and Strolin Benedetti, 1980). This new MAOI causes a moderate increase of NA, DA and especially 5-HT in the rat central nervous system. Meclobemide is rapidly and almost completely absorbed from the gastrointestinal tract and undergoes extensive ®rst pass hepatic metabolism. About 50% is bound to proteins; its clearance is almost exclusively due to hepatic metabolism and the metabolites may have no or only modest activity. The parent compound has a short elimination half-life of 1±2 h, which is lower than with other RIMAs (Amrein et al., 1989; Guentert et al., 1990), while it is of course prolonged in patients with hepatic dysfunctions (Stoeckel et al., 1990). Furthermore some studies suggested that there is no signi®cant di€erence in absorption and disposition of meclobemide between elderly people and young healthy volunteers and depressed patients (Maguire et al., 1991). Except for cimetidine, meclobemide 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

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phenylephrine; potentiation was lower when tyramine was taken with food, therefore it is recommended its administration postprandially (Korn et al., 1988). The neuroendocrine e€ects of this drug in humans are minimal, in fact a dose-related and transient hyperprolactinemia, a rise in plasma testosterone level and an increase in melatonin synthesis in pineal gland have been reported (Scheinin et al., 1990; Markianos et al., 1991; Oxenkrug et al., 1985). In depressed patients, meclobemide 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 meclobemide (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 either twice or three times daily and the treatment duration varies between 4 and 8 weeks. It has showed an antidepressant ecacy comparable to tricyclic antidepressants and newer generation antidepressants; however, further studies are needed to con®rm these promising results. Toloxatone is another reversible MAO-A inhibitor, which acts on noradrenalin and serotonin mainly. It undergoes a remarkable ®rst-pass e€ect in liver; its plasma half-life is 1±3 h. It is used at a dosage of 600 mg daily distributed in three administrations (Torta, 1999). 6.4. Mood stabilizing drugs Mood stabilizing drugs are widely used for preventing recurrences of depression and for preventing and treating bipolar illness. They include lithium, the anticonvulsants carbamazepine and valproic acid. Putative

Table 15 Pharmaceutical characteristics and mean dosage of MAOI

Phenelzine Isocarboxazid Tranylcipromine Tranylcipromine + Tri¯uperazine Clorgyline Moclobemide Broforamide Selegiline Toloxatone

Selectivity of action

Mean dosage (mg/day)

Non selective Non selective Non selective Non selective MAO-A (irreversible) MAO-A (reversible) MAO-A (reversible) MAO-B MAO-A (reversible)

15±30 10±30 20±30 10±30 300±600 10 200±600

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last generation mood stabilizing drugs include the dihydropyridine L-type calcium channel blockers, which require further clinical trials to better clarify their role and the anticonvulsants phenytoin, lamotrigine, gabapentin and topiramate, which have unique mechanisms of action and also merit further systematic study (Post et al., 1998). 6.4.1. 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). Lithium is an ion whose mechanism of action is not certain. It is administered as the carbonate or citrate salt, it is readily absorbed, distributes rapidly to liver and kidney and more slowly to muscle, brain and bone. Lithium undergoes no metabolism and is excreted by the kidneys. It enters cells via sodium channels and it is extruded by the active cation pump at about onetenth the rate of sodium so that it tends to accumulate within the cells; in fact, the thyroid gland concentrates lithium two to ®ve times higher than its serum concentration (Sanders-Bush and Sulser, 1995). It has a stabilization e€ect on neurotransmission and on receptor systems. In fact, in experimental animals lithium increases triptophan uptake and the synthesis of 5-HT and it also enhances 5-HT release, potentiating 5-HT1 receptor-mediated behaviour, whilst it seems to attenuate 5-HT2 receptor-mediated responses (Sanders-Bush and Sulser, 1995). Moreover, lithium enhances noradrenergic neurotransmission and alters phosphatidylinositol turnover, which mediates signal transduction at a number of central receptors, such as 5-HT2 a1-noradrenergic, muscarinic and glutamate receptors. The action on 5-HT function, though it is not yet well documented in humans explains its antidepressant activity and the potentiative interactions of lithium and TCAs, while other systems, in particular the in¯uence on phospatidylinositol turnover could explain its antimanic e€ects. Given its low therapeutic index, plasma concentration monitoring is essential (Salzman, 1982) and as suggested by some studies (Abou-Saleh and Coppen, 1983) adequate ecacy in elderly patients can be achieved at relatively low plasma concentrations (0.5±2 mEq/L), even because 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 have concomitant physical disease which needs the administration of di€erent medications that can disrupt water and electrolytes balance and lead to potentially hazardous ¯uctuations in lithium concentrations (De

Angelis, 1990). Moreover, lithium can interfere with renally sodium excretion, can alter thyroid function and causes heart conduction disturbances, therefore a careful drug monitoring is requested (Balant-Gorgia and Balant, 1995). Rare side e€ects are nausea, diarrhoea, 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. 6.4.2. Carbamazepine Carbamazepine (CBZ) was ®rst introduced as an antiepileptic drug in 60s. In psychiatry, it is used for treating acute mania if lithium is unsuccessful or poorly tolerated; moreover, it can be used in bipolar manic-depressive patients and if added to tryciclic antidepressants in all the patients with therapy resistant unipolar depression. CBZ has no sedative action and its activity is due to neuronal membranes stabilization, thanks to an interference with Na+ and other ion ¯uxes. CBZ absorption is slow and irregular following oral administration (Morselli and Rossi, 1982); peak concentration occurs 4±8 h after oral ingestion (Leppik, 1992). CBZ elimination is dose-dependent and varies greatly with age. It is biotransformed to CBZ 10,11-epoxide (CBZ-E), is bound to albumin and to a1-acid glycoprotein at 65±85% of the total drug. Its main side e€ects are nausea, dizziness, ataxia, visual disturbances and rarely aplastic anemia. It is a potent enzyme inducer so that it may lower levels of other drugs such as haloperidol, theophylline, warfarin, steroids and, for chronic administration, it can even induce the enzymes responsible for its own metabolism. 6.4.3. Phenytoin Phenytoin (PHT) can also be used as mood stabilizer, since it acts by stabilizing neuronal membranes (Woodburg, 1980) for Na+-ATPase inhibition, Na+entrance reduction and Ca2+-entrance decrease (Jones and Wimbihsh, 1985). PHT is absorbed slowly and incompletely after oral administration, being also in¯uenced by age-related physiologic changes. The peak concentration occurs at 3±12 h after administration (Leppik, 1992) and about 90% is protein-bound, it is mainly p-hydroxylated and conjugated to glucuronic acid before urine excretion. PTH metabolism is reduced in the elderly (Verbeeck et al., 1984), so that careful changes in the posology are needed (Perucca et al., 1984). It has dose-dependent neurotoxic e€ects, such as ataxia and impaired cognitive functions; moreover, megaloblastic anemia and changes in vitamin D metabolism with osteoporosis may occur. 6.4.4. Valproic acid Valproic acid (VPA) can also be used as mood

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stabilizer, probably for its action on Na+ currents; it inhibits GABA-transaminase and succinic-dehydrogenase, which are those enzymes involved in GABA catabolism. It is well absorbed following an oral dose and is 90% bound to plasma proteins. VPA can be metabolized either via mitochondrial mechanisms or via cytoplasmic enzymes and is dehydrogenated in 2-en, 3en and 4-en compounds. Its half-life is from 9 to 18 hr and its clearance is similar both in the young and in the elderly (Bauer et al., 1985). VPA inhibits its own metabolism and the metabolism of several drugs; PHT and CBZ increase the clearance and lower plasma concentrations of VPA. The most common side e€ects are nausea, vomiting, abdominal pain and heartburn; to avoid them a slow decrease of the dosage is requested, especially in the elderly; a severe side e€ect due to its idiosyncratic toxicity is hepatotoxicity (Porter and Meldrum, 1995). 6.4.5. Verapamil Verapamil is a dihydropyridine L-type calcium channel blocker whose mechanism in stabilizing mood is not clear. It is usually adminestered orally and has a plasma half-life of 2±8 h. Its most frequent side e€ects include postural hypotension, bradycardia, nausea, headache, weakness and constipation. Atrio-ventricular blocks are observed especially in the elderly. Verapamil should be avoided in patients treated with antihypertensive agents, b-blockers or antiarrhythmics (Dubovsky, 1986). 6.4.6. Lamotrigine Lamotrigine (LTG) is an antipeileptic whose mechanism of action is a reduction of glutamate release subsequent to blockade of voltage-sensitive sodium channels; it does not have any activity at the NMDA receptor. It has a broad spectrum of anticonvulsant e€ects and can be successfully used as mood stabilizer. The drug is almost completely absorbed and peak plasma concentrations are reached in 1±3 h; its protein binding is ca. 55%. The elimination occurs primarily by hepatic metabolism and ca. 70% of a single dose is recovered in the urine, primarily as a glucuronide conjugate. Its half-life is ca. 25 h and it follows a ®rstorder linear kinetics. Its use is limited by the presence of rash in ca. 3% of patients and it is the most common cause of discontinuation of treatment (Goa et al., 1993); other side e€ects include dizziness, headache, blurred vision, diplopia, ataxia, nausea, somnolence. 6.4.7. Gabapentin Gabapentin (GBP) is one of the new anticonvulsants which is also used as mood stabilizer, as it enhances GABA synthesis and turnover in select brain areas (Stewart et al., 1993). GBP has a plasma terminal elimination half-life of 5±6 h and the bioavailability is ca.

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59%. The major route of elimination is via renal excretion of the unchanged compound, since it is not metabolized and does not in¯uence hepatic mixedfunction drug metabolizing enzymes. The compound does not bind to plasma proteins (McLean, 1995; Vollmer et al., 1986). The undesirable e€ects are somnolence, fatigue, dizziness and ataxia, but in many cases tolerance develops rapidly to these e€ects. In elderly people with impaired renal function, GBP plamsa levels should be monitored. 6.5. Other antidepressant agents There is considerable interest in the possible antidepressant properties of antiglucocorticoids, as strongly supported by studies of the hypothalamicpituitary-adrenal (HPA) axis in depression (Price et al., 1996). Murphy et al. (1991) were the ®rst investigators to employ antiglucocorticoids in depressed patients who had no evidence of primary endocrine disease, by using at di€erent dosages aminoglutethimide, ketoconazole or metyrapone, with a response rate of 50%. HPA plays a crucial role in depression; HPA hyperactivity is initially compensatory, for example it may be a response to stress, but subsequently becomes pathogenic as a result of continuation of the stressors, genetic vulnerability, transient immunological or physiological abnormalities, or other factors (Duman et al., 1995). The most surprising ®nding is that an antidepressant activity has been suggested both for glucocorticoids and antiglucocorticoids. However, the toxicity and loss of ecacy of available agents during long term administration may constitute signi®cant limitations to their general use especially in the elderly, so that the development of new agents is requested in order to further progress in this ®eld (Price et al., 1996). 7. Electroconvulsive therapy Electroconvulsive therapy may be used in those patients in whom pharmacological therapy was not e€ective and/or have an high risk of suicide. The most common side e€ect is a transient loss of memory, which might be avoided through the stimulation of nondominant hemisphere. Moreover the increased intracranial pressure might induce the herniation of brain tissue through tentorium. All the subjects with osteoporosis may undergo fractures for convulsive movements. Further research involving randomized controlled trials are required for evaluating the ecacy of complementary and alternative therapies in the treatment of depression, such as exercise, acupuncture, relaxation therapies (Ernst et al., 1998b), while in the elderly, better if associated to a pharmacological treat-

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ment, a signi®cant role may be also attributed to psychotherapy. In particular, in geriatric patients with recurrent major depression, combined treatment of an antidepressant and interpersonal psychotherapy appears to be the optimal clinical strategy in preserving recovery (Reynolds et al., 1999).

Acknowledgements This research was supported by Ministero dell'Universita e della Ricerca Scienti®ca e Tecnologica (MURST).

References 8. 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 also derives from bipolar disorder, pseudodementia, pathological grief and organic mood disorder as those related to medications or physical illness (Casey, 1994). The diculties 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 into account before prescribing an antidepressant therapy to an old patient. Furthermore, the main aim of a pharmacological treatment of 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 at last achieved (Cassano et al., 1993). Tricyclic antidepressants are the ®rst line drugs in young people, whilst in the elderly they have to be used carefully for their important side e€ects. Nortriptyline and desipramine as well seem to be the best tolerated tricyclics in old people. However, second generation antidepressants are preferred for the elderly and those patients with heart disease as they have milder side e€ects and are less toxic in overdose (Lim, 1993). Moreover, these newer drugs, especially serotoninergic antidepressants, do not cause any disturbances of memory, as, on the contrary, all those antidepressants with a marked antimuscarinic activity do (Danion, 1993). MAOIs are useful drugs in resistant forms of depression in which the above mentioned drugs had no ecacy and the last generation drugs and in particular selective MAOIs, such as meclobemide seems to be very successful. Lithium is used especially to prevent recurrence of depression, even if its use is limited in old patients for its side e€ects. Psychotherapy is usually used as an adjunct to pharmacotherapy, while electroconvulsant therapy is used only in the elderly patients with severe depression, high risk of suicide or failed drug treatment. However, questions remain about the value of drug treatment for those depressions that are most common in late life, including those that occur in extremely old patients and in patients with signi®cant medical illness (Katz, 1993).

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