Science Space
Relationship between depression and dementia: clinical and animal behaviour studies
Dementias are a set of disorders characterised by memory impairment and at least another cognitive function, which are acquired and have negative repercussions on occupational and social capacities, not occurring exclusively in the course of delirium (American Psychiatric Association, 1994). They are one of the biggest medical problems in present times, given that they are serious diseases, the majority being progressive and incurable. Their frequency increases with age, and as a result of population ageing, their number is very likely to increase (Malgrem, 2000).
Among the several risk factors that have been identified for dementias, depression has met with controversy, as many studies backed by distinct methodologies have generated different and even opposing results (Jorm, 2001; Brodaty, 2003; Ownby, 2006). This variability seems to depend on at least five key factors: (1) lack of rigour in the diagnosis of depression, (2) the short time lapse between the two diagnoses (which does not permit answering the question whether depression is an early prodrome or a dementia risk factor), (3) non-identification of the distinct subtypes of depression, (4) non-identification of the various dementias, and (5) the wearing down of longitudinal studies.
Clarifying this relationship will give us a rationale for conceiving studies that imply dementia prevention strategies (for instance, the treatment of depression). Taking into account that most are incurable diseases, prevention is currently the only strategy.
Distinct types of depression, in particular, appear to follow different evolution types towards dementia. Should this be confirmed, they may, on a secondary level, provide data for validating the existence of these distinct types.
It has been possible to follow an initial cohort of over 300 patients set up in the 1970s and 1980s by Paes de Sousa and colleagues, eminent phenomenologists, and who had a well-defined diagnosis of depression (evaluated using psychopathological scales that differentiate each symptom, thus allowing identifying each type of depression). This cohort was compared with a group of non-depressed people who had been retrospectively identified in what concerns the evolution of dementia.
Results suggest that patients with depression evolve towards dementia more rapidly and in higher numbers, although the clinical picture appears to present some clinical and neuropsychological differences with regard to other forms of dementia.
A curious fact is that the actual personality of depressed patients (high neuroticism, low extroversion) also seems to contribute to this evolution.
These relationships mechanisms have not been totally characterized, despite most previous evidence pointing to stress and the hypothalamic-pituitary-adrenal axis. Indeed, both stress and some types of depression seem to be associated with some form of hypercortisolism, and cortisol is particularly damaging for hippocampal neurons. Various parameters associated with hypercortisolism (basal salivary cortisol, Dexamethasone suppression test etc.) are currently being tested, in collaboration with the Mood Disorders Unit of the Institute of Psychiatry, London.
On the other hand, and regardless of the mechanism, it is important to know if the cure for depression reduces the risk of dementia or cognitive decline. Antidepressants are some of the main drugs used to treat depression, but prospective studies related with the evolution towards dementia following treatment with antidepressants are difficult to conduct. Animal behaviour studies, particularly maternal separation, enable experiments by controlling a higher number of variables and using drugs, which would not be ethically possible on humans. Newborn rats have been subject to a protocol that is recognized to generate a depression phenotype (maternal separation), which has been confirmed in a classical behavioural despair test (Forced Swimming Test - FST – which measures the time the animal spends until giving up escaping from a basin full of water and just floats motionless). Antidepressants are preferably administered orally (mixed with food), and subsequently, the FST and other behavioural anxiety tests can be carried out (like the Open Field test, which measures the time the animal spends in the open part of the platform versus the time he spends in the hidden part). Other tests investigate spatial learning and memory, such as the Morris Water Maze (MWM). This test measures the time rats take to find an underwater platform not visible from the surface during 4 or 5 days (which allows drawing a learning curve). On day 5, the platform is taken away and the time rats take looking for it near the location it stood previously is measured (this is considered to be a memory test).
Acknowledgments:
I would like to thank in particular my supervisors, Professors Maria Luísa Figueira and J. Alexandre Ribeiro, and also Ms Ilda Paes de Sousa and Professor Alexandre de Mendonça, as well as the entire team of the Dementia Study Group and of the Pharmacology and Neuroscience Institute.
Among the several risk factors that have been identified for dementias, depression has met with controversy, as many studies backed by distinct methodologies have generated different and even opposing results (Jorm, 2001; Brodaty, 2003; Ownby, 2006). This variability seems to depend on at least five key factors: (1) lack of rigour in the diagnosis of depression, (2) the short time lapse between the two diagnoses (which does not permit answering the question whether depression is an early prodrome or a dementia risk factor), (3) non-identification of the distinct subtypes of depression, (4) non-identification of the various dementias, and (5) the wearing down of longitudinal studies.
Clarifying this relationship will give us a rationale for conceiving studies that imply dementia prevention strategies (for instance, the treatment of depression). Taking into account that most are incurable diseases, prevention is currently the only strategy.
Distinct types of depression, in particular, appear to follow different evolution types towards dementia. Should this be confirmed, they may, on a secondary level, provide data for validating the existence of these distinct types.
It has been possible to follow an initial cohort of over 300 patients set up in the 1970s and 1980s by Paes de Sousa and colleagues, eminent phenomenologists, and who had a well-defined diagnosis of depression (evaluated using psychopathological scales that differentiate each symptom, thus allowing identifying each type of depression). This cohort was compared with a group of non-depressed people who had been retrospectively identified in what concerns the evolution of dementia.
Results suggest that patients with depression evolve towards dementia more rapidly and in higher numbers, although the clinical picture appears to present some clinical and neuropsychological differences with regard to other forms of dementia.
A curious fact is that the actual personality of depressed patients (high neuroticism, low extroversion) also seems to contribute to this evolution.
These relationships mechanisms have not been totally characterized, despite most previous evidence pointing to stress and the hypothalamic-pituitary-adrenal axis. Indeed, both stress and some types of depression seem to be associated with some form of hypercortisolism, and cortisol is particularly damaging for hippocampal neurons. Various parameters associated with hypercortisolism (basal salivary cortisol, Dexamethasone suppression test etc.) are currently being tested, in collaboration with the Mood Disorders Unit of the Institute of Psychiatry, London.
On the other hand, and regardless of the mechanism, it is important to know if the cure for depression reduces the risk of dementia or cognitive decline. Antidepressants are some of the main drugs used to treat depression, but prospective studies related with the evolution towards dementia following treatment with antidepressants are difficult to conduct. Animal behaviour studies, particularly maternal separation, enable experiments by controlling a higher number of variables and using drugs, which would not be ethically possible on humans. Newborn rats have been subject to a protocol that is recognized to generate a depression phenotype (maternal separation), which has been confirmed in a classical behavioural despair test (Forced Swimming Test - FST – which measures the time the animal spends until giving up escaping from a basin full of water and just floats motionless). Antidepressants are preferably administered orally (mixed with food), and subsequently, the FST and other behavioural anxiety tests can be carried out (like the Open Field test, which measures the time the animal spends in the open part of the platform versus the time he spends in the hidden part). Other tests investigate spatial learning and memory, such as the Morris Water Maze (MWM). This test measures the time rats take to find an underwater platform not visible from the surface during 4 or 5 days (which allows drawing a learning curve). On day 5, the platform is taken away and the time rats take looking for it near the location it stood previously is measured (this is considered to be a memory test).
Acknowledgments:
I would like to thank in particular my supervisors, Professors Maria Luísa Figueira and J. Alexandre Ribeiro, and also Ms Ilda Paes de Sousa and Professor Alexandre de Mendonça, as well as the entire team of the Dementia Study Group and of the Pharmacology and Neuroscience Institute.
Frederico Couto
fcouto@fm.ul.pt