J.H.K.C. Psych. (1993) 3, 51-58

ORIGINAL ARTICLE

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INTRODUCTION

It is estimated that from the year 1986 to 2006, the life expectancy in Hong Kong will improve from 74.0 years in men and 79.8 years in women to 77.3 and 82.9 respec­ tively (Tam, 1990). The population of those aged 65 or over will increase from 8% to 13% of the total population, or from 0.42 to 0.81 million in the same period (Census and Statistics Department, 1987). Of such a geriatric population, about 10% will suffer from mild to moderate dementia (Hollisters, 1985). And approximately 50-60% of this patient population are presently believed, at least in western countries, to suffer from senile dementia of the Alzheimer's type (Alzheimer's disease of AD) (Rogers, 1986). Caring for AD patients will also produce a huge burden on the community unless effective therapies are identified.

Management of AD patients includes social, psychologic­ al and drug approaches, Many different categories of drugs are being tried recently and show variable degrees of effec­ tiveness in improving the cognitive functions of AD pa­ tients, This article thus aims to review the mechanisms proposed and clinical efficacy observed of the many types of drugs that have been tried.

One possible therapeutic strategy that has been investi­ gated extensively is based on the hypothesis that AD is associated with decreased central cholinergic transmission. There are large reductions in the activity of choline acetyl­ transferase in the cortex and hippocampus of brains from AD patients (Roberts, 1989). Thus the potentiation of cen­ tral cholinergic function by cholinergic drugs might amelio­ rate the cognitive impairment in AD.

DRUGS ACTING ON THE AUTONOMIC NERVOUS SYSTEM

DRUGS ACTING ON THE PARASYMPATHETIC SYSTEM

(1) Acetylcholinestemase inhibitors

9-ANMIN0-1, 2, 3, 4-TETRAHYDROACRIDINE (THA)

One of the major chemical changes in AD is the de­ crease in activity of choline acetyltransferase in the cerebral cortex and hippocampus, leading to an impairment of acetylcholine syntheses (Katzman, 1986). THA was original­ ly developed as a partial antagonist of morphine, appears to have acetylcholinesterase inhibiting effects (Kaul, 1962) and has been tried in various studies as a potential treat­ ment of AD.

Other than being an enzyme inhibitor, THA was found to have other mechanisms to explain its cholinergic effect. In electrophysiological studies with neurons of Lymnaea stag­ nalis, THA inhibits the slow outward K+ current and conse­ quently increases the duration of the action potentials (Dru­ karch, 1987). Moreover, THA concentration-dependently inhibits the uptake of noradrenaline, dopamine and seroto­ nin. Such uptake inhibition does not seem to occur at the level of the axonal membrane, but at the level of the monoaminergic storage granules (Drukarch, 1988). Thus THA might well have some monoaminergic effect.

The initial report by Summers et al (1986) that combined oral treatment of THA and lecithin improves the condition of patients with AD has attracted considerable interest. La­ ter studies, however, failed to demonstrate such marked improvements. A study using THA 125mg/day showed that when compared to placebo, THA does not improve either the Mini-mental State score nor the Stockton Geriatric score except a slight but statistically significant improve­ ment in the physician's score on the Visual Analogue Scale (Chatellier, 1990). It was concluded that neither short term nor long term treatment with oral THA in dosages lower than 125mg/day improves the ymptoms of AD.

In another similar study (Fitten, 1990), only 3 patients out of 9 continuing in long term treatment of 125mg/day showed measurable cognitive improvement, of which only one displayed clinically obvious improvement

Other than the dosage of THA, adding lecithin to the regimen may also be of importance. Initially Summers et al used a lecithin dose of 10.9g/day. A later study showed that the regimen of lOOmg/day THA and 4.7g/day lecithin failed to demonstrate any significant clinical benefit in AD patients (Gauthier, 1990).

Several reasons have been proposed to explain the negative results of these studies, small sample size being an important one in many of them. Moreover, many of the subjects chosen for study were already in an advanced stage of the disease (Fitten, 1990). Lastly, multiple transmit­ ter deficits as well as a loss of neurons in critical areas of the brain are probably present in AD. Counteracting the former alone by THA may not bring about clinically de­ monstratable benefits (Gauthier, 1990).

There is also a high incidence of side effects in the use of THA. Autonomic symptoms such as gastrointestinal dis­ turbance and hypotension have been shown in four-fifths of 54 patients and hepatotoxicity in one-third (Gauthier, 1988). Actually, a large multicentre trial in the States was discontinued because of the high incidence of hepatotoxic­ ity, although it subsequently resumed (Matsuyama, 1988). Such hepatotoxicity seems to take the form of an auto­ immune granulomatous hepatitis, which is reversible on stopping the drug (Byrne, 1989).

The therapeutic index of THA is so small that it is absolutely critical and difficult to find the best dose, for pa­ tients vary greatly in their responsiveness (Marx, 1987).

PHYSOSTIGMINE

Several studies found consistent, albeit quite modest, im­ provement in the neuropsychological test performance of AD patients after IV infusion of physostigmine (Christie, 1981; Davis, 1982; Blackwood, 1986). In a study to com­ pare clinical effects by different routes of administration, intra-cerebroventricular seems to be the most promising, with oral and single dose IV showing only modest and short-lasting effects. In addition, side effects, mainly nausea and dizziness, occurred more by oral and IV administration (Becker, 1988).

Another study showed that oral long-term physostigmine therapy causes significantly better memory test scores than short-term, and the benefit can be sustained for up to a year in some patients (Stern, 1988). 4-AMINOPYRIDINE 4-aminopyridine (4-AP) has similar mechanism as THA, namely blocking potassium channels in axon terminals (Glover, 1982) so that the action potential is prolonged. In one study, there is a suggestion of some efficacy in improv­ ing memory and learning (Wesseling). In a later study, (Davidson, 1988) however, results indicated no significant difference in the 4-AP phase and the placebo phase. Un­ selective release of neurotransmitters by 4-AP, poor penetration into the CNS and the presenile onset of the disease in the subjects are possible explanations of the lack of a positive result.

(2) Acetylcholine analogues

CARNITINE

Acetyl-1-carnitine is structurally related to acetylcholine and appears to either act upon neural transmission and/ or influence neuronal metabolism (Rai, 1990). Placebo­ controlled trials have shown an improvement of the P300 potential, which is an indicator of associative and cognitive processes and latency in decision-making processes (Testa, 1982). A 6 month double-blind trial in 50 patients also showed improvement in the Blessed Dementia Scales (Mantero, 1986).

A recent double-blind, placebo-controlled study showed less deterioration of the reaction time in the computerized classification test in the active treatment group (Rai, 1990). However, owing to the small number of subjects (20 com­ pleted the trial), the difference failed to reach statistical sig­ nificance. Side effects are mild and include nausea and vomiting.

And as mentioned before, L-carnitine was shown to nor­ malize abnormal properties of fibroblasts from patients with AD in an in vitro system (Malow, 1989).

(3) Muscarinic agonists

INTRACEREBROVENTRICULAR BETHANECHOL

Trials of intracerebroventricular (ICV) infusion of bethanechol demonstrated feasibility of the drug delivery technique but did not document objective improvement in cognitive functions (Harbaugh, 1984, 1985). A double­ blind placebo-controlled crossover study demonstrated a significant improvement in Mini-mental State scores but also significantly slowed down the performance on Trials A testing during drug infusion (Harbaugh 1989). Altogether there was 1 death in 68 patients due to post-operative pneumonia, 7 developed seizures, 3 had pump packet in­ fection and another 3 with Parkinsonistic signs. In another controlled clinical trial, Parkinson's disease as a side effect was diagnosed and confirmed at autopsy (Fox 1989).

It was suggested, however, that most of the side effects are associated with the cortical biopsy and though !CV bethanechol has just modest beneficial effects, this method of drug delivery is still potentially valuable (Harbaugh, 1989).

Another difficulty of the use of ICV bethanechol is the narrow therapeutic window for positive effects. While low dose (0.35mg/day) does not reliably alter patient function­ ing, moderately increased dose appears to have a palliative effect on patient's mood and behaviour, but high dose (1.75mg/day) is detrimental to the patient's functioning (Penn, 1988).

The basic assumption of !CV administration, that poten­ tial problems of blood-brain barrier penetration can be cir­ cumvented, has also been challenged. Placing drugs into the ventricles does not necessarily assure better access to the brain, since the drug still has to be distributed through the CSF and reach the target nerve cells (Whitehouse, 1988).

ARECOLINE

Arecoline, a cholinergic agonist, has been shown to cross the blood brain barrier easily when administered peripher­ ally (Herz, 1967). In a pilot study, no statistically significant improvement in performance on most cognitive tasks was observed at any dose, although marginal improvement in picture recognition ability and in ratings of word-finding were observed at the lower dose (0.Smg/hr for 1-6 hrs) (Tariot, 1988).

RS-86

RS-86 (2-ethyl-8-methyl-2, 8-diazospiro-[4.5]-decan-1, 3- dion hydrobromide) is a selective muscarinic agonist. In a double-blind placebo-controlled study, RS-86 lOmg/day, in combination with a peripherally active anticholinergic glyco­ pyrrolate 6mg/day, showed no consistent, clinically signifi­ cant cognitive improvement (Mouradian, 1988). The nega­ tive finding might be due to the concomitnat stimulation of Ml and M2 muscarinic receptors by RS-86 and that some M2 tone might minimize its beneficial action at the post­ synaptic Ml receptors (Palacios, 1986).

(4) Nicotinic agonists

Studies with nicotine and smoking in humans suggest that nicotine may improve the speed, accuracy of informa­ tion processing and long-term memory as well as produc­ ing state-dependent learning (Jones, 1990). In a study to examine the direct nicotinic augmentation of central cho­ linergic functioning in AD, cognitive tests showed a de­ crease in intrusion errors on a dose of 0.25mg. However, significant dose-related effects of anxiety and depression were noted (Newhouse, 1988).

Thus central nicotinic cholinergic stimulation deserves further investigation as a potential treatment strategy of AD.

(5) Beta-carbolines

It has been proposed recently that antagonist be_ta­ carbolines may be effective in treating AD patients as they can disinhibit the remaining cholinergic neurons of the bas­ al forebrain (Procter, 1988). The mechanism is simple. There is now considerable evidence that benzodiazepines impair cognitive functions (Robbins, 1988). Beta-carboline compounds while acting as benzodiazepine/GABA receptor complex antagonists, there by enhance the cortical cho­ linergic function by inhibiting an inhibitory GABAergic in­ fluence on the cholinergic cells (Robbins, 1988).

ZK 93426, a partial antagonist, has been shown to have significant effects on measurements of vigilance and atten­ tion as well as small beneficial effects on visual recognition memory in normal young human volunteers (Robbins, 1988). However, so far, no clinical trials on AD patients has been done.

DRUGS ACTING ON THE SYMPATHETIC SYSTEM

CLONIDINE

Apart from cholinergic deficiency, a deficiency in cortical noradrenergic innervation has also been described in AD. Neurochemical findings show depletion of noradrenaline, its synthesizing enzyme dopamine beta-hydroxylase, and its metabolite 3-methoxy-4-hydroxyphenyl-glycol in the cere­ bral cortex (Rossor 1986), while neuropathic observations indicate a neuronal loss in locus coeruleus, which provides noradrenergic innervation to the cerebral aortex and hippo­ campus (Marcyniuk, 1986).

A double-blind, placebo-controlled therapeutic trial with clonidine hydrochloride, a centrally active noradrenergic receptor agonist, however, showed no statistically signifi­ cant changes in the cognitive functions of AD patients (Mohr, 1989).

GUANFACINE

Guanfacine, when compared to clonidine, is a more selective centrally active alpha-2 agonist which produces much less sdeation (Sorkin, 1986). In a clinical trial using 1.2mg/day, neuropsychological testing failed to reveal any significant atten uation of cognitive deficits, Examination of the mood state, however, indicated a small but consistent improvement (Schlegel, 1989).

As both the cholinergic and noradrenergic projections to the cerebral cortex appear to be damaged in AD, it has been suggested that some combination of agonists of both types might confer the greatest functional benefits to the patients (Schlegel, 1989).

OTHER CATEGORIES OF DRUGS

(1) Nootropics and metabolically active compounds

Nootropic agents are drugs which enhance learning and memory, facilitate flow of information between the cerebral hemispheres, and enhance the general resistance of the brain to physical and chemical injuries, while lack the usual psychological and cardiovascular activities of other psychiatric agents (Nicholson, 1988). They do not have a well-defined mechanism of action.

The prototype nootropic agent is piracetam. It may have some of its effects by enhancing acetylcholine . release (Koppelman, 1986). Clinical evidence for its effectiveness, however, is lacking. While an earlier study reported that 80% of dementia patients showed improvement in mental state (Faleni, 1974), a double-blind, placebo-controlled cli­ nical trial of piracetam 2.4g/day showed that although attention is improved, none of the cognitive variables is en­ hanced (Stegaink, 1972).

Among the most commonly used metabolically active compounds are dihydroergotoxine (DHET) and vinca alka­ loids. DHET has been shown to inhibit cerebral cyclic nuc­ leotide phosphodiesterase activity and to influence central monoaminergic systems (Nicholson, 1988). Clinical trials in­ dicate that DHET produces small but consistent improve­ ment in dementia patients (McDonald, 1979).

Vinca alkaloids increase cerebral blood flow and glucose utilization. Like DHET, they also inhibit cyclic nucleotide phosphodiesterase (Hidaka, 1984). In clinical trials, vin­ pocetine, the prototype agent, was found to be superior to placebo in demented patients (Nicholson, 1988).

A compound recently undergoing clinical evaluations is denbufylline. It inhibits cAMP-specific-cyclic nucleotide phosphodiesterase and thus elevates cAMP levels (Challis, 1988). In a clinical trial, improvements in demented pa­ tients' conditions were significantly better than with placebo (Nicholson, 1988).

(2) Thyrotrophin-releasing hormone

High dose thyrotrophin-releasing hormone (TRH) infu­ sions were thought to maximize central nervous system effects and potentially produce facilitation of cholinergic function (Mellow, 1989). In a clinical trial, with TRH 0.3mg/kg, AD patients showed statistically significant in­ crease in arousal and improvement in affect as well as a modest improvement in sematic memory. Such a dose of TRH produces only transient rises in systolic blood pres­ sure, with no effect on diastolic blood pressure, heart rate or temperature (Mellow, 1989).

(3) ACTH-fragments

It is known that ACTH and its moieties have positive effects on different learning and memory tasks (Pancheri, 1984). The effect might involve decrease in CSF beta­ endophin (beta-EP), beta-lipotropin (beta-LP) and ACTH levels (Facchinetti, 1984). The proposed mechanism is that the N-terminal ACTH fragments could represent the endo­ genous antagonists of the opiate system. They occupy the opiate receptors and stimulate the release of Cortico­ tropin Rleasing Factor (CRF). And as recent evidence correlates the cortical CRF deficit with the impaired choline acetyl-transferase activity in AD patients (De Souza, 1986), N-terminal ACTH fragments could reverse the situation.

A clinical trial using N-terminal ACTH fragments for 14 days on AD patients, however, showed no change in cognitive functions. A significant increase in CSF beta-EP was found, while ACTH and beta-LP levels remained un­ affected (Nappi, 1988).

(4) Naltrexone

It was discussed before that endogenous opiate antago­ nists could stimulate the release of CRF and thus reverse the impaired choline acetyltransferase in AD patients. Thus naltrexone, an exogenous opiate antagonist, might have similar effects.

In clinical trials, naltrexone elevates the plasma cortisol in normal elderly patients (Leslie, 1985). In contrast, the corti­ sol response to naltrexone is absent in AD patients. In addi­ tion, cognitive functions do not seem to be affected (Pomara, 1988).

Although naltrexone used alone is not a good treatment for AD, the blunted neuroendocrine responses it brings about are worth further investigations.

(5) Imipramine

25% of AD patients might meet DSM-III criteria for a major depressive disorder (Reifler, 1982). Drug treatment in these patients is difficult. On one hand, cognitive functions might improve if the depression is the source of the cogni­ tive impairment (Kiloh, 1961). On the other hand, the anti­ cholinergic properties of imipramine might aggravate the cholinergic deficits in AD (Loebel, 1989).

In a randomized double-blind study, scores on the Hamilton Rating Scale for Depression indicated significant improvement in AD patients. Measures of cognitive func­ tions were inconsistent. It was thus concluded that depress­ ion in AD patients is a treatable condition. Moreover, the depression is mostly mild to moderate and with judicious monitoring, imipramine does not noticeably aggravate the condition of AD patients (Reifler, 1989).

(6) Haloperidol

Neuroleptic drugs are used commonly in demented pa­ tients for the management of symptoms like suspiciousness, hallucination and emotional Iability (Raskind, 1987).

However, their efficacy is not well established and little is known about their side effects.

In a recent pilot study, haloperidol 1-Smg/day was used in 9 AD patients who had psychosis or behavioural disturb­ ance. It was found that patients could not be maintained on more than 4mg/day due to the severity of extrapyra­ midal side effects. Moreover, Modified Mini-mental State scores worsened while taking haloperidol (Devanaud, 1989). Thus the side effects and decline in cognitive func­ tion may compromise the efficacy of the use of neuroleptic drugs in AD patients.

(7) Amantidine

Amantidine. a dopaminergic agonist, is used in the treat­ ment of Parkinson's disease, In AD patients with psychotic features, the use of haloperidol might lead to a dystonic reaction with tonic flexion of the trunk to one side and slight axial rotation in the absence of other dystonic symp­ toms (Davidson, 1988). The term Pisa syndrome has re­ cently been coined for such type of dystonic reaction (Guy, 1986). Thus in AD patients with psychotic features, a regi­ men of haloperidol 6mg/day and amantidine 200mg/day has been suggested and a case report showed marked amelioration of the psychotic features without any dystonic reaction (Davidson, 1988).

(8) Thiamine

Studies have indicated that the activities of thiamine­ dependent enzymes are reduced in the brains of AD pa­ tients (Sheu, 1988). In a double-blind, placebo-controlled, crossover pilot study, oral thiamine 3g/day was tried in AD patients with no stigmata of thiamine deficiency. Global cognitive ratiing by the Mini-mental State Examination was higher but behavioural ratings did not differ significantly (Blass, 1988).

CONCLUSION

Many types of approaches have been tried in the drug treatment of AD. An objective comparison of the results of the clinical trials must be based on reliable dignostic criteria. The finding that some physicians, even when using a fixed set of dignostic criteria, display low levels of inter­ rater reliability indicates that documentation and further training to establish interrater reliability are important in studies where different observers are used to diagnose AD (Kukall, 1990).

Through many clinical, physiological and biochemical ways are available to evaluate the drug efficacies, care must be taken when using them to ensure a good correla­ tion between these indexes and the real improvement of the patients psychologically and in their daily social activi­ ties.

The therapeutic strategy that has been most extensively investigated in the recent years is based on the cholinergic hypothesis. However, in most clinical trials using either anticholinesterases, acetyl-choline analogues, muscarinic or nicotinic agonists or beta-carbolines, only modest improve­ ments are seen in a portion of AD patients.

Such results do not necessarily reflect defects in the cho­ linergic hypothesis. Administration of precursors like lecithin may not be able to increase central acetylcholine effectively. Anticholinesterases would be expected to de­ crease in efficacy as the disease progresses owing to a loss in the number of surviving neurons (Fitten,1990). Lack of effects of muscarinic agonists like arecoline could be attri­ buted to their very rapid metabolism or to stimulation of presynaptic muscarinic autoreceptors (Nordstrom, 1980). Even when bethanechol is administered intracere­ broventricularly, this does not necessarily mean that it can diff use effectively from the cerebrospinal fluid into the brain (Whitehouse, 1988). Moreover, m uscarinic and nicotinic re­ ceptors also occur at many other locations in the body. Thus the many undesirable effects may lead to a very nar­ row therapeutic window (Roberts, 1989).

As for developments of cholinergic therapy in the future, transplants of foetal cholinergic cells might be possible (Arendt, 1988). Peripheral effects of muscarinic agonists could be reduced by non brain-penetrating antagonists with little side effects like constipation caused by the present antoagonists. Low-efficacy muscarinic agonists might also selectively influence "memory" (Roberts, 1989).

Studies with muscarinic antagonists show that there might be three types of muscarinic receptors (Caulfield, 1983). Ml-sites predominantly located in the cortex and hippocampus might be Ml-selective (Roberts, 1989). The future developments in the field of cholinergic therapy of AD thus have a great potential (Wurtman, 1990).

Other categories of drugs also deserve further investiga­ tions. Metabolically active compounds and thyrotropin­ releasing hormone produce small but consistent improve­ ment in the cognitive function. Studies on antidepressants show that the depressive element in AD is treatable if the dosage is carefully monitored. Such improvement in affect may also have beneficial effects on cognition. Neuroleptic agents can remove the psychotic features in some patients and the concomitant extrapyramidal side effects might be controlled by amantidine. Moreover, studies of these many types of drugs also help to unveil the neuroendocrinologic­ al and biochemical aspects of the aetiology of AD.

Finally, though this article is dedicated to the medical aspects of management, it must be stressed that other aspects of psychosocial management of AD patients are equally, if not more, important (Gelder, 1989). AD patients cannot be managed satisfactorily in the traditional one-to­ one psychiatrist-patient relationship and the attending psychiatrist should be part of an multi-disciplinary team (Weiner, 1989). Moreover, owing to the increasing geriatric population and the need for continuous management, much of the diagnostic and therapeutic load will rest on the primary health carers and an efficient health delivery sys­ tem and good professional training of such carers are as important as the ongoing clinical therapeutic trials.

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Antonio AT. Chuh MBBS, LRCP (Edin), LRCS (Edin), LRCPS (glasg) Medical officer, TB & Chest Service, Department of Heath,99, Kennedy Road , Hong Kong.

*Awarded the Wu Chung Prize 90/91 as medical student.