The concept of core depression

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While most agree that depression is a heterogeneous condition, there have been innumerable attempts to subdivide depression according to symptom patterns. Relevant to this chapter, most studies of depression have identified a group of patients characterised by certain symptoms: early morning waking, weight loss, poor appetite, anhedonia, and agitation. This symptom grouping has been variously labelled as endogenous, nuclear, and melancholic depression. Early conceptualisations of this category noted that they were said to show a preferential response to physical treatments, and to show more dysfunction of biological correlates of depression, such as the DST. Few good studies have made direct comparisons between melancholic depression and other types, preventing firm conclusions from being drawn. However, many of the studies referred to in this chapter have tended to select patients with more melancholic features, and how applicable the findings are to the more common but less severe cases remains unknown.

Psychotic depression

The clinical importance of separating out psychotic depression relates to the preferential response of this group to antidepressant-antipsychotic combinations or electroconvulsive treatment (ECT). In terms of neurobiology, some authors have argued that psychotic depression represents a separate and distinct category, based on clinical, genetic, treatment response and biological features. There is some evidence that there may be biological differences between psychotic depression and non-psychotic depression in terms of a more disturbed HPA axis (see above), increased dopamine turnover (that is, higher HVA levels in the CSF), and different patterns of disturbance of serotonin pathways (Wheeler Vega et al., 2000). Overall, however, a separation on the basis of neurobiology remains premature.

Atypical depression

Atypical depression has been used in the past to mean a number of different conditions, including non-endogenous depression, depression secondary to another condition, depression associated with anxiety or panic, and depression with reversed biological features. However, as the concept has evolved, atypicality has been more tightly defined, and the disorder is now included in DSM-IV.


Atypical depression does appear to be a valid concept. Sullivan and colleagues (Sullivan et al., 1998) used data from the large US National Comorbidity Survey, and identified six syndromes, two of which correspond to mild atypical depression and severe atypical depression, respectively. A study of 1000 female twin pairs also found an atypical depression syndrome; furthermore, individuals tended to have the same syndrome on each recurrence, and the concordance of syndrome type was greater in monozygotic than in dizygotic pairs (Kendler et al., 1996).


In view of the relatively recent addition of atypical depression to the psychiatric nosology, few data exist on the similarities and differences between typical and atypical depression. One of the most frequently observed differences relates to the HPA axis. While hyper-cortisolaemia is characteristic of melancholic major depression (see above), several studies have now suggested that atypical depression is associated with hypocortisolaemia. Gold and colleagues have suggested that, while typical major depression can be characterised by an excessive activation of both the physiological stress systems, the locus ceruleus-noradrenergic

Table 2.3 Organic causes of a depressive syndrome


Infections: Neurological:




disorders of cortisol, thyroxine or parathormone production;

hypopituitarism; hypoglycaemia glandular fever, syphilis, AIDS, encephalitis stroke, Parkinson's disease, multiple sclerosis, brain tumours (classically meningioma), trauma, cerebral lupus common non-metastatic manifestation, especially pancreatic carcinoma, which may otherwise remain occult, and lung carcinoma deficiencies of folate, nicotinamide (pellagra), and vitamins

B12, B1 (thiamine), and B6 cerebral ischaemia, myocardial infarction system, and the HPA axis, the opposite changes are present in atypical depression (Gold et al., 1995). Some support for this is provided by studies showing that the control of noradrenergic function is relatively preserved in atypical compared to typical depression (Asnis et al., 1995). Gold and colleagues suggest that it is diminished central CRH activity that is specifically related to the symptoms of hypoarousal of the syndrome (Gold et al., 1995). Evidence that it is low CRH rather than low cortisol that is related to the atypicality syndrome comes from one detailed study of Cushing's syndrome, in which cortisol is high and CRH low, where atypical depression was the predominant depressive syndrome (Dorn et al., 1995). Studies of serotonergic function are lacking, though one study suggested that platelet serotonin function is unaltered in atypical depression (Owens & Nemeroff, 1994).

Post-partum and seasonal depression

Post-partum depression and seasonal depression represent other specifiers used in the DSM-IV classification. There are some suggestions of particular biological therapeutic modalities for seasonal depression (light therapy) and post-partum depression (oestradiol). However, there are few indications that post-partum depression or seasonal depression represent biologically distinct subtypes.

Depression as a result of organic illness

There are a number of systemic diseases in which depression may be a presenting feature or a common accompaniment (over and above the 'normal' rate of depression). These are shown in Table 2.3. Drugs that may cause or exacerbate depression are shown in Table 2.4.


We can attempt to integrate the neurobiological findings in depression to the 'whole' in several ways. These include integrating neurobiological with other levels of understanding or research modalities, linking neurobiology to treatment, and attempting to relate the neurobiological changes to each other.

Table 2.4 Drugs associated with depressive syndromes


methyl-dopa, reserpine, beta-blockers, clonidine,

diuretics, digoxin


steroids, combined oral contraceptive (high dose)


L-Dopa, bromocriptine


pentazocine, indomethacin, chloroquine,


On withdrawal:

psychostimulants (e.g., amphetamines, cocaine),



cause and consequence

This chapter has already given some examples of how the biological models of depression can be tied in with other characteristics of depression from other disciplines such as epidemiology. The predisposition to suffer depression entailed by childhood experiences can be paralleled by the presence of 'endocrine scars'. Acute and chronic stress from the environment can be shown to have profound neurobiological correlates. High cortisol levels are associated with cognitive dysfunction (Van London et al., 1998). Recent neuroimaging studies reveal a brain that is overresponsive to unhappy stimuli and underresponsive to happy ones (Elliott et al., 2002). It is easy to see how such a brain dysfunction can be linked to the perceptual biases in depression, and also to cognitive theories of depression in which such cognitive distortions are felt to be a primary disturbance in depression.

Neurobiology may have relevance to the choice of different treatments available. For example, certain neurobiological disruption, such as a disrupted HPA axis or shortened REM latency, may be associated with a preferential response to physical rather than psychological treatments (Thase et al., 1993; 1996). Exciting enquiries are now being made into whether neuroimaging can inform the response to therapy. In what promises to be the beginning of a series of studies, two papers report changes in brain function occurring during treatment of depression with either psychological therapy or drug therapy. Brody et al. (2001) took 24 subjects with unipolar major depression and obtained resting PET scans of glucose metabolism at baseline and after 12 weeks of treatment with either interpersonal therapy or paroxetine. With treatment, both groups showed a similar tendency for baseline abnormalities to normalise, although the paroxetine-treated subjects had a greater decrease in depression scores. This differential response and the lack of randomisation at baseline mean that there may be explanations other than the different treatments for these changes. A second paper measured brain blood flow, using SPET, in 28 patients with major depression (Martin etal., 2001). In this case, subjects were randomised—receiving venlafax-ine or interpersonal therapy—with scans being repeated at 6 weeks. Once again, the antidepressant group had a larger fall in depression scores. On this occasion, the two treatments produced a differential change, with the venlafaxine-treated group showing posterior temporal and right basal ganglia activation, whereas the IPT group had limbic, right posterior cingulate, and right basal ganglia activation. Thus, both treatments caused basal ganglia activation, whereas only interpersonal therapy showed limbic blood-flow increase. Problems with this trial include the short duration of treatment, probably before the main effects of psychological therapy would have been detectable.

Certain treatments have a more fundamental basis in neurobiology than others. One of the more controversial treatments in psychiatry is psychosurgery. This is now only very rarely used as a last resort, in cases of severe, intractable depression under strict controls.

Stereotactic techniques are used for more specific ablation, and a variety of operations have been developed to focus on limbic areas and their cortical connections. Clinically, approximately one-third of patients are reported to gain marked benefit, though the side effects can include frontal lobe syndromes and epilepsy. There has been recent interest in deep-brain stimulation in neurology and psychiatry: implanted electrodes can induce functional lesions, but have the advantage over psychosurgery of being reversible if not successful. The advances in the understanding of the neural basis of depression outlined in this chapter may allow an informed refinement of these techniques for those unfortunate cases of severe and resistant depression.

Finally, it is worth reminding ourselves that separate biological systems do not act independently. Neurochemical systems modulate the activity of each other, endocrine systems act on neurochemical systems, neurochemical activation leads to intracellular activation, and so on. Understanding the different changes in parallel and on several levels is rarely undertaken, and this remains a huge obstacle at present to a full understanding of the neurobiology of mood disorders.

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