VIEWS & REVIEWS

Antidepressant therapy may lift more than just spirits

-Marl ill Cal/agher-

In addition to reducing depression, serotonergic therapy may also improve the cognitive performance of elderly patients with dementia. Accordingly, researchers arc considering serotonergic agents as a viable alternative to existing cognithe disorder treatments. Delegates at the 3rd President's Workshop of the Collegium Internationale Neuro-Psychopharmacologicum (CI'\P) held in Capri, Italy, earlier this month, heard evidence of the beneficial effects of the newer serotonergic antidepressants and serotonin] antagonists in patients with dementia.

The concentr:.!tion of serotonin in cortic:.!l and basal ganglia areas of the brain decreases by almost )Oo/r hetween fiO-90 years of age Intercqingly. [he concentration of the end-metabolite 5-hydroxy­Il1dokacetic acid (5-HIAA) IS nut reduced.

As serotonin is largely (If neuronal origin. this suggests that the number of nerve terminals decreases . while metabolism in the remaining terminals is increased to maintain normal 5-HIAA concenil lliJUIIs.

The decline in the number of serotonergic neurons that is seen with age is also seen in patIents with dementia. Thus. selective serotonin reuptake inhibitor (SS RI) antidepressants have been proposed as a possible treatment for cognitive disorders.

Citalopram improves cognitive function ... The SSRI citalopram [Cipramil®; LundbeckJ

significantly improved parameters slich as emotional bluntness. confusion and depressed mood in 78 elderly patients with probable Alzheimer's disease or vascular dementia. noted Dr Carl Gotrfries from the University of Gbteborg in Sweden . Citalopram 10-30 mg/day was given to patients for 4 weeks. and improvment was measured using the Gottfries-Bril.ne-Steen (GBS) scale.

In another study. 133 elderly patients with depressed mood and mild or moderate dementia had significant improvement in both depressive symptoms (on the Hamilton Depression Rating Scale) and intellectual function (on the G BS scale). The 6-week treatment was well tolerated .

Dr Gottfries felt that other SSRls may also be beneficial in the treatment of dementia. and that combination with a cholinergic agent may produce "' ....... _ ~ _ __ .. .... _ ~ cJ::: ,._ CO'COII 101COdlCOI COlllLdL).

... and may avert institutional care It appears that citalopram can also delay the need

for institutional psychogeriatric care. Evidence in support of this came from J multicentre study co-ordinated by Dr Teuvo Koskinen at the Uni­versity of Kuopio. Finland. with the assistance of researchers from Lundbeck .

A total of 183 patients aged 2 65 years with depression (DSM-III-R) and dementia disorders at 38 Health Centers were followed for up to 6 months. Depressed inpatients and outpatients with or without dementia were included. All patients received citalopram 10-30 mg/day. No other anti­depressant medication was allowed. but stable

ISSN 0156-2703/93/0522-003/$100~ Adls International Ltd

doses of benzodiazepines and anti psychotics were permItted.

The reduced need for care was identified by documenting social support. counselling. psycho­therapy. nursmg home service and hospitalisation requirements. Patients were also assessed using global ratings and GBS scores hefore and after treatme nt.

SerotoninJ alltagonists show promise Serotoninl antagonists may improve cognitive

performance by increasing the release of acetyl­choline from cortical tissue.

Unlike the serotonergic system. which is impaired in Alzheimer's disease and ageing. the brain's serotoninl system appears to remain relatively intact in patients with cognitive disorders. For example, a normal density of serotoninl receptors has been found in post-mortem samples of brain tissue from patients with Alzheimer's disease .

Therefore. it has been suggested that administer­ing serotoninl antagonists may overcome the inhibitory tone on acetylcholine release and enhance cognitive performance. Dr Cliff Preston from Glaxo. UK. described 2 clinical studies examining these potential effects of se rotonin, antagonists.

In the first study. 232 patients with age­associated memory impairment were randomised to receive either ondansetron [Zofran®; Glaxo J or placebo for 12 week s. The doses of ondansetron were 10. 250 and 1000llg po bid. Cognitive performance was assessed at 4-weekly intervals using a computerised battery of te sts designed to assess aspects of learning and memory relevant to daily life .

AftCi 12 \.\t'eeks. ondansetron 250j..ig produced significant improvements over placebo on 2/5 primary outcome measures . Ondansetron I Ollg had no significant treatment effects. while the 1000llg dose produced earlier effects which declined by the end of treatment.

'Serotonin3 antagonists may offer a nore/ strategy for the treatment of cogniti~'e

disorders such as Alzheimer's disease.' Dr C PreSIon. Claro. CK

In the second study. with a 4-way. placebo­controlled. crossover design. 20 healthy male volunteers were tested in the scopolamine model of cognitive disorders with alosetron [GR 68755:

INPHARMA~22 May 1993

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VIEWS & REVIEWS

Glaxo: phase II . This serotonin I antagonist is to times more potent than ondansetron. Patients received IV alosetron 10 and 250llg. This treatment was found to attenuate the effects of scopolamine 011 verbal and spatial memory tasks. but did not intluence the sedation produced by scopolamine.

The combination of an SSRI and a serotoninl antagonist may provide better results .

Moclobemide has slight effect Koche's antidepressant mociobemide iAurorix~l

is a reversible inhibitor of monoamine oxidase­type A (RIMA). Preclinical research indicated that moclobemide has positive effects on learning and memory. RIMA antidepressants increase sero­tonergic neurotransmission and influence the cholinergic system, which is reported to be

impaired in cognition disorders such as Alzheimer's disease.

Dr Amrein from Hoffmann -La Roche. Switzerland. presented details of a multicentre . double -blind. placebo-controlled study of moclobemide in 709 elderly depressed patients (544 female and 165 male) . Two-thirds of patients had primary depression with secondary cognitive impairment: the remainder had primary dementia and associated depression.

Not surprisingly. moclobemide demonstrated a clear antidepressant effect in all patients . There was also a slight positive effect on cognitive deficits. hut this was modest and likely to be a phenomenon secondary to the antidepressant and drive enhancing effect of the drug.

22 May 1993 INPHARMA" ISSN 0156·2703/9310522·004/$1 .00" Adl. International Ltd