Drug treatment of late-life depression or schizophrenia is of great importance, as the functional psychoses are among the most common psychiatric diseases in the elderly. It therefore seems astonishing that there are great deficits in the drug research that has been done with this age group. There are almost no studies specifically on the treatment of late-onset depression or schizophrenia. A few studies have evaluated the efficacy and safety of different antidepressants in elderly patients with depression, but there are extremely few on the efficacy and safety of neuroleptics in elderly patients with schizophrenia.
There is a broad consensus that the drug treatment of depression or schizophrenia in the elderly is in general both effective and safe. However, a high percentage of functional psychiatric diseases go unrecognised and untreated in the elderly. In consequence, longer hospital stays and increased morbidity and mortality from medical illness and from suicide may occur.
Pharmacokinetics in elderly patients
The drug treatment of elderly patients has to take into consideration certain pharmacokinetic alterations with age ().
The chief features examined here are: absorption, distribution, metabolism, and excretion (). All these processes may be affected in the elderly but the degree to which they are affected greatly varies in individual cases.
Absorption may be reduced owing to reductions in gastric acid production, in gastrointestinal motility, in gastrointestinal blood flow, and in absorptive surface. These processes are counteracted by a reduced first-pass clearance in the liver.
Distribution depends on body mass, which, as a rule, is reduced in the elderly, so that a higher tissue concentration should be expected for a given dose. The proportion of adipose tissue is also important. This proportion is increased in the elderly, which leads to a higher plasma concentration of water-soluble drugs and to the reverse effect for lipophilic compounds. Antidepressants are usually the latter. Most studies have shown a decline in plasma albumin with age, which can result in an increased free concentration of acidic drugs.
Metabolism mainly takes place in the liver. Drugs with a high hepatic excretion ratio depend on liver blood flow. This is reduced in the elderly, so that clearance may also be reduced. Drugs with a low hepatic excretion ratio are less affected by liver blood flow, but are more dependent on drug-metabolising capacity. This capacity is reduced in the elderly for processes like oxidation, reduction and hydrolysis, but not for reactions like conjugation (sulphate, glucuronide).
Excretion mainly concerns glomerular filtration, which falls by about half in old age. Compounds which are detoxified by renal elimination are therefore excreted much more slowly in the elderly.
The following study illustrates such alterations. Nies et al (1977) studied the relationship between age and plasma levels of amitriptyline and imipramine and their respective metabolites, nortriptyline and desipramine. Participants in the six-week, double-blind study of amitriptyline were depressed out-patients (n=35), whose ages ranged between 21 and 68 years. They were given 75 mg/day amitriptyline for the first five days, and that dose was subsequently increased to 150 mg/day. The imipramine study consisted predominantly of depressed in-patients (n= 23), whose ages ranged between 27 and 78 years. Most of these received 150 mg/day for a minimum of 21 days. Steady-state plasma levels of amitriptyline and imipramine showed a significant positive correlation with age; i.e. the levels were higher in older individuals. Levels of desipramine were also higher in the elderly; those of nortriptyline were not. Wide inter-subject variability was observed ().
There have been only a few reports on the relationship between plasma levels of neuroleptics and ageing in patients with schizophrenia, and these have reported inconsistent findings. Some authors found an age-related increase in the plasma levels of neuroleptics, while others did not ().
Pharmacodynamic changes in elderly patients
In vivo alterations to pharmacodynamics are difficult to demonstrate, as a synopsis of relevant studies in the literature attests. At the centre of pharmacodynamic changes in the elderly is a concept of gradual reduction of homeostatic reserve or ability to cope with environmental changes (Swift, 1990). For example, advancing age has been shown to increase the number of corrective movements involved in standing upright and has been related to a reduction in the number of dopamine D2 receptors in the striatum (). An increased sensitivity of older patients to postural hypotension induced by drugs with alpha-adrenoreceptor-blocking effects (e.g. tricyclic antidepressants) can be related to changes in the responsiveness of baroreceptors in the carotid sinus and elsewhere ().
Although the mechanism is unknown, it is well established that the elderly are more sensitive to the effects of acute doses of benzodiazepines than are young subjects. The effects of single oral doses of temazepam, nitrazepam, diazepam and others on psychomotor performance and other subjective measures have been shown to be accentuated despite similar total and free plasma levels of drug in young and old subjects (). On the other hand, long-term administration of benzodiazepines apparently causes little psychomotor impairment, despite relatively high daytime plasma concentrations ().
As a consequence of the alterations in old age mentioned above, most compounds have longer half-lives in elderly patients and can demonstrate stronger effects. As a general prescribing rule, elderly patients should receive doses of one-half to two-thirds of the doses that are usual in young patients.
Selections from the book: “Late-Onset Mental Disorders: The Potsdam Conference” (1999)