Sieglinde Modell and Florian Holsboer

Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, 80804 München, Germany

Abstract: Depression is characterized by a group of varying symptoms and encompasses a number of clinical diagnosis. External stressors usually trigger the onset of depression and the hypothalamic-pituitary-adrenocortical (HPA) axis is activated. Moreover, genetic influences play a substantial role. A large number of clinical and preclinical studies investigating the stress system in depth have led to the formulation of the corticosteriod receptor (CR) hypothesis that implies that a disturbed CR signalling is a pathological mechanism leading to enhanced CRH release. Almost all antidepressants irrespective of their pharmacology at the receptor level have an influence on the HPA system suggesting a common mode of action. Therefore the stress system is a promosing candidate for further development of new drug targets for the treatment of depression and other stress-related disorders.


Depression is one of the most disabling diseases worldwide, not only in industrialised countries associated with a stressful life style, but even more in poor countries, where malnutrition and infections render the brain more susceptible to mental disorders. In the United States, the 12-month prevalence in the general population is 10.3% rising up to a life time prevalence of 17% (Kessler et al, 1994). It is prognosticated that regarding the duration and severity, depression will become the second leading course of disability in the year 2020 (Murray and Lopez, 1997), trailing only ischaemic heart disease. Depression itself, however, is associated with an increased risk for the development of cardiovascular diseases (Glassman and Shapiro, 1998). Those patients that develop depression after having suffered from a myocardial infarction have a 3—4 times higher mortality rate during the 6 months following the event.

■"Corresponding author. Present address: Neuroscience Bristol-Myers Squibb Sapporobogen 6-8, D-80809, Munich, Germany. Tel.: +49+89/12142-203; Fax: +49+89/12142-301; E-mail: [email protected]

One of the most serious complications of depression is suicide, which is attempted by 15% of the patients. Approximately 10% of all suicide attempts lead to death, accounting for over one million deaths per year. In the population below 40 years of age, suicide is the second leading cause of death following car accidents in industrialised countries.

Despite these high numbers and the many years and resources that have been put into research regarding the cause of depression and the development of new treatment strategies, knowledge of the pathophysiology of affective disorders is still poor.

One of the most promising approaches at the moment is the neuroendocrine hypothesis of depression. By this concept many clinical signs can be explained and a common pathway for the efficacy of antidepressant drugs with various modes of action could be postulated.

Historical aspects

Already Hippocrates proposed a relationship between humoral fluids and the occurrence of 'melancholy' meaning 'black bile'. In the ancient world, it was believed that a pathological amount of black bile led to the mood aberrances. Therefore, drugs with a dehydrating effect like hellebore were used until the 19th century.

Manfred Bleuler has been the first to systematically investigate the complex association between hormones, mood and behaviour. Bleuler (1919) showed that patients with a primary endocrine disorder, e.g. a hyper- or hypo-function of the thyroid system and especially excessive Cortisol levels, have a high incidence of psychiatric disorders, above all depression. The correction of excessive hormonal secretion or the supplementation of hormone deficiencies led to an improvement not only of the metabolic symptoms but also of the associated psychopathological signs.

In the past 20 years, a large amount of evidence has been established that shows that neuronal circuits in the brain regulate the secretory activity of endocrine glands. On the other hand, the brain itself is a major target of hormonal activity in the body.

With the development of antidepressants, research focussed on the metabolism of biogenic amines and the capacity of their respective receptors to alter intracellular signalling pathways that ultimately induce changes in gene activity. The fact that antidepressants have effects on presynaptic uptake transporters and metabolic enzymes led to the noradrenaline and serotonin hypothesis of depression.

Already before the discovery of antidepressants in the 1950s, it was known that depression is associated with increased levels of circulating stress hormones, and Bleuler even suggested at that time hormone treatments as potential antidepressants. This view, in fact, was uttered by S. Freud some time before. The hormonal changes seen among depressives, however, were regarded as being epiphenomena due to the stressful experience of suffering from a depressive episode. Also, results from life event research led into this direction since it became clear that many depressive episodes, especially at the onset of the disease, i.e. the first episodes, are preceded by external stressful life events resulting in increased stress hormone levels.

In the past decade, however, a vast amount of evidence from several research groups accumulated indicating that altered stress hormone secretion in depression is not epiphenomenal but linked to the causality of the disease. Antidepressants, despite their varying biogenic amine receptor interaction, may have a common mode of action by normalising a dysregulated stress hormone system and, in consequence, the neuronal circuits that regulate these neuroendocrine functions may become potential targets for the development of new psychotropic drugs (Holsboer and Barden, 1996).

Clinical description

The term 'depression' summarises a group of clinically very heterogeneous signs and symptoms. Major depression that affects about 10% of the population can be characterised as a life time illness with about 70% having repeated exacerbations without prophylactic treatment (Frank, 1999). Patients suffer from intense anxiety, feelings of worthlessness and recollections of past failures and helplessness. They show lack of motivation despite a subjective feeling of unrest. Concentration, memory and perceptivity are impaired. The mood is depressed sometimes with a diurnal variation in severity. Lack of appetite and weight loss can be very prominent mimicking, e.g. cachexia due to cancer. Sleep is severely impaired with early morning awakening and disturbances in the REM/non-REM sleep structure. In more severe cases, psychotic symptoms can occur in the sense of delusional beliefs, e.g. that the distress suffered is a punishment for sinful past actions or completely unrealistic fears concerning the financial situation of the patient.

Bipolar illness or manic-depressive illness is a further type of depressive disorders affecting about 1-2% of the population world-wide. Depressive episodes alternate with manic episodes on an irregular basis. Sometimes, there are healthy intervals between a manic and a depressive episode that can last several months or even years, in other cases, there is a direct switching between the two psychopathological states that in its extreme form may cycle several times per day ('ultra-rapid cycling'). Manic episodes can be described as the opposite of depression. Patients with mania have an elated mood, increased self-esteem with feelings of omnipotence. Their drive is greatly increased leading to a carelessness with their financial situation sometimes leading to a large sum of debts. Due to their increased libido, they indulge, in a risky sexually promiscuous behaviour.

Another symptom cluster has been summarised under the term 'atypical depression'. In addition to dysphoria and anhedonia, patients describe a feeling of disconnectedness to the outside world and emotional emptiness. They avoid contact with others and feel tired very easily. The somatic symptoms of atypical depression in the contrary to melancholia are characterised by fatigue, sleepiness and increased food intake resulting in weight gain (Horwath et al, 1992).

Patients with dysthymia, another diagnosis belonging to the group of alfective disorders, present typical depressive symptoms that last more than two years ongoing without a clear cut episodic course. They have less symptoms that are usually not as severe as in major depression.

Despite of all efforts to establish a system that allows to diagnose an affective disorder according to exact criteria, the clinical routine teaches a different lesson. Patients very often have comorbid diagnosis, like anxiety disorders or the clinical feature changes during the course of the illness. Patients with dysthymia for example, may suffer from additional full blown major depressive episodes and vice versa.

Up to now, the rigid diagnostic entities according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the International Classification of Diseases (ICD-10) that follows similar categories seem rather arbitrarily chosen, and one may speculate that these varying symptom clusters could rather fit into a concept of an 'affective disorder spectrum' with mild and short-term brief depression on the one hand and severe bipolar or schizo-affective disorder on the other hand (Fig. 1).


Stressful life events as a trigger for an alfective disorder have been a major topic for psychiatric epidemiology (Paykel et al, 1969, 1994). Life changes requiring social adjustments have been found to be predictive for depression and suicide attempts. Especially unpleasant life events involving personal loss, like separations, divorce or a death in the family can lead to depressive symptoms, whereas stressful life events involving a threat, e.g. becoming attacked or victim of a crime, and the serious medical illness of a partner, predicted symptoms of anxiety (De Beurs et al, 2001). But not only life events that were immediate antecedents of the onset of depression should be taken into consideration. There have been a number of studies suggesting that early-life trauma like bereavement or separation precipitates depressive illness in later life (Heim et al, 2000). Especially, the death of a parent before a child is 17 increases the risk for adult depression (Lloyd, 1980). This effect was amplified when these persons encountered a further trauma in adulthood, indicating that early stress sensitised these subjects to later stress.

Since it is widely reported that major depression has a higher prevalence in women compared to men, Kendler et al. (1993, 2001) have tried to differentiate between the type and amount of stressors in male and female patients. Women reported more problems in getting along with individuals in their proximal network and higher rates of housing problems and loss of confidants. Men were more prone to work problems, job loss or legal problems.

Depressed meed Depressive Hinor Re^fent healthy persons personality depression depression depression

S,aadmpd=d ' depression

Fig. 1. Affective spectrum disorders. Clinical signs of depression show a broad variety of diagnosis ranging from mild depression on one side to severe psychotic disorders on the other side.

Moreover, they had a higher depressogenic effect of divorce and separation, a finding that could explain the greater mortality in widowers compared to widows (Zisook and Downs, 2000). However, there was no difference in the rates or sensitivity to stressful life events that could explain the gender difference. It might be that not the amount or type of the stressors is different, but that the recall and reporting of these events and of depressive symptoms in general are more pronounced in women compared to men.

The association between a major psychosocial stressor and the onset of major depression decreases, at the number of episodes increase. Post (1992) described this as an effect related to the biology of sensitisation and kindling, where a shift from externally triggered episodes to those that occur autonomously, takes place (Fig. 2).

To find out how stressful life events interact with genetic risk factors, twin pairs that were interviewed four times over a 9-year period were investigated. The kindling effect was the strongest in those with a low-genetic risk, indicating that patients who have a high-genetic risk may be under influence of a 'pre-kindling effect' that leads to a depressive episode also at the beginning of the illness even with minor stressors or no stressors that precede the onset. Additionally, those probands with a high-genetic risk showed a higher frequency of stressful life events due to their probability to select themselves into high-risk environments likely to produce stressful life events and increase their vulnerability to major depression (Kendler et al., 1999).


Since many years and numerous family, twin and adoption studies it is clear that genetic factors play a substantial role in the etiology of mood disorders. Relatives of index patients are more affected by the disease than the general population. The pre-morbid risk found in varying studies for first-degree relatives of affectively ill probands ranges from 6 to 40% (McGuffin and Katz, 1989). Monozygotic twins have a concordance rate that is about 2-5 times greater than the dizygotics suggesting strong genetic factors. Also, adoption studies have contributed to these evidences by showing that biological relatives of adoptees with affective illness have an 8-fold increase in depression and a 15-fold increase in suicide compared to the relatives of matched control adoptees (Wender et al, 1986).

During the past 10 years, more than 20 susceptibility loci for affective disorders have been published (Craddock, 1999). However, only very few genes with mutations contributing significantly to selected symptoms like anxiety or response to treatment of depression have been identified, such as the serotonin transporter gene (Lesch, 1996) or the tyrosine hydroxylase gene (Meloni, 1996), but all with modest contribution. One of the most promising approaches to come closer to the identification of susceptibility genes is the integration of traits that are more directly connected to the underlying neuropathology than the diagnosis also called endophenotype in genetic studies (Freedman, 1997).

The Munich Vulnerability Study on Affective Disorders has been trying to identify possible

Clinical condition depressed

Genetic Susceptibility

Exogenous factors

Clinical condition depressed

Genetic Susceptibility

Exogenous factors

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