Mohammed T. Abou-Saleh

398 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYHYPOTHALAMIC–PITUITARY–ADRENAL (HPA)AXISDepression across the age range is associated with hyperactivityand dysregulation of the HPA axis, characterized, in part, byelevated plasma and urinary cortisol, increased corticotropinreleasinghormone (CRH), blunted corticotropin (ACTH)response to CRH and resistance of cortisol to suppression bydexamethasone. Increased cortisol secretion is probably the mostconsistently observed physiological abnormality in patients withmajor depression (see Chapter 81 on dexamethasone suppressiontest).Total urinary free cortisol may reliably distinguish depressedfrom non-depressed individuals in clinical studies of mixed-agedadults. The levels of cortisol, furthermore, appear to correlatewith the severity of depression, the presence of psychotic features,and with cognitive impairment 17 . Anatomical imaging researchshows correlations of cortisol with brain ventricular enlargement18 .One way in which aging and depression may interact is asfollows. It is possible that normal aging is associated withenhanced limbic–hypothalamic–pituitary–adrenal axis activity,possibly due to age-associated neuronal degeneration in thehippocampus. The neuronal degeneration, in turn, may resultfrom increased levels of glucocorticoids associated with bothdepression and aging. Depressive illness in the elderly mayexacerbate this condition, as may repetitive stressful life events.PLATELET MONOAMINE OXIDASE (MAO)ACTIVITYMAO catalyses the oxidative deamination of several monoaminesand exists in two forms, identified by relative substrate specificity.In the brain, both MAO-A and MAO-B are present; in platelets,only MAO-B is present. In the brain, MAO-B may be moreresponsible for the degradation of dopamine and MAO-A fornorepinephrine.Platelet MAO activity increases with age, nearly doublesbetween ages 30 and 80, and is higher in females than males 19 .Platelet and brain MAO-B activity is increased in AD, over andabove the increase associated with age 20,21 . Some medicalconditions, including liver disease, anaemia, epilepsy and cancer,are also associated with increased MAO activity, whereas indiabetes this may be lower 7 . Although not specific for a particularpsychiatric disorder, differences in platelet MAO activity seem todistinguish certain depression populations. Among subgroups ofmixed-age, depressed subjects, MAO activity has been reported tobe higher in primary depressed, non medically-ill outpatients thanin controls, and also higher in secondary than in primarydepression 22,23 . MAO activity may not distinguish endogenousfrom non-endogenous or delusional from non-delusional depression22 , but it may be lower in bipolar compared with unipolardepression 24 .Post mortem studies of MAO in the brain have shown that thequantitative distribution of MAO-A in brainstem monoaminenuclei is normal in major depression 25 . However the density ofbrain MAO-B in suicide victims showed a positive correlationwith age, but was not different between suicides and age-matchedcontrols 26 .Elderly female inpatients with primary, unipolar depression,predominately endogenous, whose illness onset was in mid-life,may have lower platelet MAO activity than either later-age-onsetdepressed females of controls 27 , suggesting that despite similarclinical presentation, decreased MAO activity may be associatedwith early-onset depression in the elderly. On the other hand, inelderly depressed female outpatients, MAO activity was higherthan controls, but age of onset was not assessed 28 . In a depressedpopulation, lower platelet MAO activity predicted the occurrenceof neurotic depression (ICD-9) 10 years later 29 .In a group of elderly, depressed outpatients, higher plateletMAO activity was correlated with anhedonia, anxiety, a positivefamily history of depression and response to MAO inhibitors 30 .Depressed patients with reversible cognitive impairment havehigher MAO activity than depressed patients without cognitiveimpairment 31 . Also, among elderly outpatients, MAO activity wasincreased in a group with depression secondary to mental illnesscompared with a primary depression group 32 . Thus, changes inplatelet MAO activity are complex among the elderly depressedpopulation.Platelet MAO activity may serve as a vulnerability marker forpyschopathology in general. Association studies suggested that inthe population with age over 40 years, presence of the 165 bp alleleof DXS7 at the MAO locus was significantly associated withunipolar depression 33 . Both high- and low-MAO activity areassociated with increased risk of bipolar disorder, depression andalcoholism in family members.SEROTONINDeficits in the serotonin neurotransmitter system have beenimplicated both in major depression and in suicide. Numerousstudies have demonstrated an association between low platelet5-HT uptake and depression and a recent study showed higheruptake efficiency in depressed patients with high net uptake ratebut similar 5-HT content to normal controls 34 . Many studiessuggest that the serotonin metabolite 5-hydroxyindole acetic acid(5-HIAA) is decreased in the CSF of depressed patients;presynaptic serotonin function is decreased as well 35 . Specificbrain 3 H-imipramine binding sites are correlated with serotoninpatterns of innervation and are located on presynaptic serotonergicnerve terminals 36 . The active component for this binding sitehas a role in modulating neuronal serotonin uptake. Amongsuicide victims, at least, there is evidence for a decrease in thenumber of imipramine receptors 35 , and an increase in the numberof postsynaptic serotonin 2 receptors 37 . This latter finding mayrepresent upregulation due to decreased intrasynaptic serotonin.The role of 5-HT has also been investigated in genetic,neuroimaging, neuroendocrine and post mortem studies. Serotonintransporter gene polymorphism was not associated with oldagedepression 38 . However, in patients with Parkinson’s disease,those with the short allele of the 5-HT transporter promoterregion—associated with low 5-HT transporter density—hadhigher depression and anxiety scores than those without thispolymorphism 39 . Secondary depression to Parkinson’s disease,stroke and Huntington’s disease in the elderly is associated withlow cerebral blood flow and metabolic rate in orbital frontalcortex and basal ganglia, suggesting that, as in primarydepression, there is disruption in cortical–basal ganglia–thalamicneuronal loops 40 , abnormalities that are under 5-HT control 41 .Poststroke depression is associated with blunted prolactinresponse to buspirone indicating low 5-HT activity 42 . Serotonintransporter density, measured using paroxetine binding inmidbrains of suicides with major depression, were comparableto values obtained in normal controls 43 .Although a considerable literature evaluating CSF markers inmixed-age depressed and suicidal patients exists, only one studyhas focused specifically on elderly depressed subjects. In thisstudy, both CSF 5-HIAA and the dopamine metabolite homovanillicacid (HVA) were lower in elderly depressed patients whoattempted suicide than in depressed non-suicidal patients andcontrols 44 .