Arch. Gerontol. Geriatr. suppl. 6 (1998) 65-70 0167-4943/98/$19.00 0 1998 Elsevier Science Ireland Ltd. All right reserved 65

BRAIN SEROTONIN AND THE MECHANISM OF ACTION OF SELECTIVE

SEROTONIN RE-UPTAKE INHIBITORS (SSRI)

M. CASACCHIA, R. POLLICE, M. MATTEUCCI and R. RONCONE

Chair of Clinical Psychiatry, University of L’Aquila, Ospedale S. Salvatore, Viale Nizza, I-60100 L’Aquila, Italy

SUMMARY The role of serotonin [5-HT) in the human central nervous system and its

involvement in a variety of physiological and behavioral functions are summa- rized. The main items of the 5-HT hypothesis of depression, and the role of 5-HT in the pathophysiology and treatment of this mood disorder are considered. The main pathogenetic hypotheses and drug treatment of depression are also briefly reviewed. New data on the administration of selective 5-HT r-e-uptake in- hibitors (SSRI) and their mechanisms of action are discussed. Their relative safety, and the lack of cognitive impairments associated with their use are in favor of their utilization in the treatment of older patients. However, it is emphasized that evidence-based treatment strategies of depression in the elderly patients have not yet been identified and this lack of scientific evidence might be associated with the problem of under-diagnosis and under-treatment in the daily medical practice. Finally, the recent guidelines of pharmacological treatment strategies of depression in the elderly people are reported, emphasizing the specific issues in treating older patients, such as the bio-availability, the pharmacokinetic changes, the excretion rates of medicines, etc., which all need to be conisdered when planning treatment of depression.

Keywords : elderly depression, serotonin, antidepressant drug therapy, selective serotonin re-uptake inhibitors (SSRI)

INTRODUCTION

In central nervous system [CNS) serotonin (5-hydroxytryptamine, 5-HT) is

an important neurotransmitter involved in a variety of physiological and behavi-

oral functions ranging from the control of sleep and wakefulness, feeding, ter-

moregulation, cardiovascular function, emesis, sexual behavior, spinal regulation

of motor function, emotional and psychotic behavior, and drug-induced halluci-

natory states.

The levels of 5-HT in the CNS only represent about l-2 % of the total a-

mount of 5-HT found in the human body. The indole-amine compounds cannot

cross the blood-brain barrier, and hence all the neuronal S-HT in the CNS is

synthesized locally. 5-HT is formed by a two-step process involving the hydr-

oxylation of the essential amino acid L-tryptophan to 5-hydroxytryptophan (S-

HTP), which is then decarboxylated to 5-HT. It is now well established, more-

over, that there are multiple 5-HT receptors in the peripheric and central neu-

rons : currently the number is about 14 and there has been a consequent deve-

lopment of numerous compounds with relative specificity for one or more of those

receptor subtypes (Lerer et al., 1996; Duman et al., 1997).

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5-HT is localized within specific neuronal pathways, the cell bodies are to

be found in discrete brain nuclei, the midbrain and brain stem raphe nuclei.

During the last 20 years, information about the role of 5-HT pathway in the con-

trol of physiological and behavioral functions has expanded, largely based on a

growing understanding of the 5-HT metabolism in the nerve endings and on the

development of drugs that interfere with this process. One of the major events

in this process was the development of drugs interfering with this process. One

of the major events in this process was the development of compounds preventing

the enzymatic inactivation, or the re-uptake of 5-HT released from the nerve

endings and the finding that such drugs possess antidepressant effects.

Early studies demonstrated that 5-HT was found in substantial amounts in

cat and dog brain but with regional variations: the limbic regions showed espe-

cially high S-HT levels, indicating an involvement in emotional behavior. The

best evidence suggests that depression, particularly when linked with suicidal

behavior, is associated with reduced serotoninergic function in limbic areas, al-

though it is far from being clear which specific 5-HT receptors subtypes are in-

volved (Duman et al., 1997).

5-HT IN THE PATHOGENESIS AND TREATMENT OF DEPRESSION

The 5-HT hypothesis of depression has been formulated in different ways.

One version of this hypothesis is that a deficit in serotoninergic activity is a

proximate cause of depression. Another version is that a deficit in serotoninergic

activity is important as a vulnerability factor in depression. A third hypothesis,

by now only of historical interest, attributed increased vulnerability to major de-

pression to enhanced serotoninergic activity.

The last review of these hypothesis concluded that the available data con-

firm the role of 5-HT in pathophysiology and in the treatment of depression.

Early studies indicated that agents depleting monoamines could lead to depression

in a small percentage of individuals and the reduced availability of 5-HT could

play a role in the formation of depression. However, despite extensive research,

it remains unclear whether long-term antidepressant treatments result the in-

creased or decreased function of the many monoamine pathways located through-

out the brain. Other studies demonstrate that, although the depletion of 5-HT

does not lead to depressive symptoms in normal individuals, patients having been

treated with selective 5-HT reuptake inhibitors (SSRI) are vulnerable to relapse.

This indicates that 5-HT is somehow involved in the maintenance of an antide-

pressant response, but can explain alone neither the mechanism of action of an-

tidepressant treatments nor the pathophysiology of depression (Lerer et al.,

1996).

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The activation of monoamine receptors is a consequence of antidepressant

treatment and elevated levels of 5-HT. Perhaps the persistent activation of these

receptors would lead to adaptations in the receptors, which would then contri-

bute to the delayed therapeutic action of antidepressant treatments. Recent stu-

dies, indeed, demonstrated that long-term antidepressant treatments downregula-

te the presence of receptor sites for 5-HT. Other data led to various receptor

sensitivity hypotheses; for example that the action of antidepressant treatments

is dependent on the down-regulation of beta-adrenergic receptors of 5-HT2 re-

ceptors, and it may lead to depression. Another hypothesis was formulated on

S-HTlA receptor sensitivity: long-term antidepressant treatments increase the

function of postsynaptic S-HTlA receptors in the hippocampus (Duman et al.,

1997). This could occur by either the increased sensitivity of postsynaptic

5-HTlA receptors or desensitization of 5-HT autoreceptors. Another possibility is

that increased 5-HTlA neurotransmission is necessary, but insufficient, for an-

tidepressant efficacy and that the activation of additional factors is required.

Finally, long-term adntidepressant treatments could result in the sustained ac-

tivation of the intracellular signal transduction cascades that mediate the actions

of monoamine receptors. This could include the activation of 5-HT receptor sub-

types that are not themselves regulated by antidepressant treatments. It will be

important in the future to determine which 5-HT receptors mediate the therapeu-

tic actions of antidepressant treatments.

However, the best evidence suggests that depression, especially when lin-

ked with suicidal behavior, is associated with reduced serotoninergic function in

limbic areas, but it is yet unclear which specific 5-HT receptor subtypes are

involved (Lerer et al., 1996).

Finally, age-related decline in central serotoninergic function may make ol-

der individuals more vulnerable to depression and possibly render depressive

episodes more frequent, more severe and less amenable to treatment.

5-HT RE-UPTAKE INHIBITORS IN THE TREATMENT OF ELDERLY DEPRESSION

A wide variety of management options are available for the treatment of de-

pression. Antidepressant drugs currently in use include well-established tricyclic

antidepressants (TCA] and monoamino-oxidase inhibitors (MAOI), an important

group of SSRI and a new, selective, reversible inhibitor of monoamino-oxidase

(RIMA), moclobemide.

Generally, in elderly patients the same principles of antidepressant drug

treatment apply as for younger people. Obviously, there are some particular

problems in treating older patients which need to be considered when planning

individually the treatment.

For example, appreciation of the age-associated changes in the bio-availabi-

lity of antidepressants is important when treating older patients. The aging pro-

cess is associated with changes in the pharmacokinetic characteristics of anti-

depressant drugs, including altered absorption, distribution, metabolism and ex-

cretion of medications.

Usually, SSRI molecules are well tolerated by older subjects and most stu-

dies suggest similar efficacy and time course of action to TCA. SSRI increases

the synaptic concentration of 5-HT, probably by binding to the modulatory site

identified using imipramine or paroxetine. The consequence of that increased sy-

naptic concentration of 5-HT is the activation of the S-HTlA and lB/lD recep-

tors, leading to decreased neuronal firing and terminal release. After chronic

treatment, the net effect of the change in synaptic 5-HT and the activation of

the autoreceptors will determine the pharmacological actions that are important

for the antidepressant properties of the SSRI. Functional studies on the 5-HTlA

receptors indicate that chronic uptake inhibition decreases the functional state of

the 5-HTlA somatodendritic autoreceptor (Tannock and Katona, 1995; Heeren et

al., 1997). A consequence of this is an increase in the release of 5-HT from

terminals in forebrain regions. Thus the major effect of chronic SSRI treatment

is to increase presynaptic release of 5-HT which is then available to act on

postsynaptic 5-HTlA receptors. In this respect postsynaptic 5-HTlA receptors

may be of importance as electrophysiological studies have shown, enhancing re-

sponsiveness after chronic SSRI.

The SSRI compounds are free of anticholinergic (i.e., these drugs result in

less cognitive impairment) and antihistaminergic effects; they are also free of

cardiotoxicity and do not cause postural hypotension. This fact results in better

tolerability and better compliance. The main side-effects seem to be headache and

nausea, which may be minimized by slow dose escalation (Reynolds et al., 1992).

SSRI may be more rapidly effective in reducing suicidal thoughts, and this is

particularly important in the perspective that suicide rate is relatively higher in

the elderly.

One of the most studied SSRI compounds in the elderly is paroxetine, which

is a highly selective drug. Despite it does not seem to be any difference in to-

lerability between the majority of SSRI, paroxetine was associated with signifi-

cantly more rapid response and greater cognitive improvement. Moreover, it has

less anticholinergic side effects than TCA and low doses may be effective in the

elderly: its dosage ranges from 10 to 40 mg/day (Dunbar et al., 1995).

Also sertraline, fluoxetine and fluvoxamine seemed to be effective in the

treatment of elderly depression, at a dosage of 25 to 150 mglday. 5 to 20

mglday, and 50 to 150 mglday, respectively (Newhouse, 1996). Recently, cita-

lopram has been suggested in the treatment of elderly depression (at a dosage

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up to 20 mg/day) because of its attractive pharmacokinetic profile and especially

of the low potential for interaction with other drugs (Cottfries, 1996). These

new generations of antidepressant drugs may reasonably be considered as drugs

of first choice, even though it must yet be estimated whether the cost-benefit

ratio is favorable.

Although newer antidepressants have not shown an overwhelming advantage

compared to the older ones, their relative safety and the lack of cognitive im-

pairment associated with their use, may justify their utilization as main drugs in

the depression of an elderly population (Kasper et al., 1995). Finally, the high

risk of recurrence of depression in old age can be significantly reduced by con-

tinuous prophylactic treatment, since a rather high percentage of partially reco-

vered patients was recently found (Heeren et al., 1997). In fact, the combina-

tion of low expectations of treatment and fear of vigorous treatment, together

with the lack of clear guidelines for treatment strategies, may unduly influence

the treatment of depressive illness in the elderly (Heeren et al., 1997).

CONCLUSIONS

The absence of evidence-based treatment strategies for depressive illness in

late life may result in under-treatment in daily practice. This is probably due

to both the lack of scientific data concerning the best treatment strategies and

the complicated treatment because of intolerance of drug side-effects and somatic

comorbidities (Brodaty et al., 1993: Blazer, 1994). Finally, tendency of physi-

cians to treat the elderly patients less aggressively than younger subjects can

lead to the premature conclusions that elderly patients are treatment-resistant. It

can be suggested that depression in elderly people should be vigorously treated.

indeed, drug selection should be based on relative risk vs benefits, keeping in

mind that older people are more sensitive to antidepressant drugs because their

elimination half-life is prolonged.

Further studies on elderly patients older than 80 are needed in order to

better understand the specific therapeutic drug strategies. However, the last

reviews propose the following pharmacological treatment strategies for depression

in elderly people, as guidelines: (i) Desipramine and nortryptyline of the TCA,

are preferred for their efficacy on symptomatology and their wide range of the-

rapeutic doses, always remembering that the plasma levels are not helpful in mo-

nitoring the dose efficacy. [ii) MAOI are effective in elderly, but orthostasis

and drug/food interactions are troublesome especially in outpatients. (iii) Tra-

zodone and bupropion may be useful but dosing schedules are needed. (iv) SSRI

compounds can be considered effective and safe.

Antidepressant drugs, both in elderly and younger patients, should be con-

sidered as only a part of a holistic approach, and it should always be kept in

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mind that symptom’s relief is not the only outcome for elderly persons suffering

from depression.

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