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There is evidence that abnormalities in the level or function of the serotonin (5-
hydroxytryptamine, 5-HT), norepinephrine and dopamine neurotransmitters acting on central
nervous system neurons may be important in the pathophysiology of depression, although this
evidence is inconclusive. Animal studies indicate that serotonin is intimately involved in the
regulation of the sleep–wake cycle, appetite, sexual behavior and aggression. Patients with major
depression appear to have abnormal serotonergic neurotransmission (see Figures 7.6–7.8). Some
of these abnormalities (such as increased numbers of platelet and brain 5-HT2 receptors) appear
to be linked to suicidal or impulsive behavior, rather than to the depressive syndrome per se. The
results of neuroendocrine studies suggest that depression is associated with decreased
neurotransmission at postsynaptic 5-HT1A receptors (see Figures 7.9 and 7.10). Many
antidepressants are thought to produce their therapeutic effects by acting upon these postsynaptic
5-HT1A receptors. Depression is also associated with increased 24-h adrenocorticotropic
hormone (ACTH) levels, as well as elevated urinary and plasma cortisol levels. Exogenous
administration of ACTH leads to a greater release of cortisol whilst the patient is depressed,
suggesting a statedependent oversensitive adrenal gland (Figure 7.11). Recent research indicates
that depression is associated with enlargement of the adrenal glands, which shrink in size
following adequate treatment. Some of the changes in brain 5-HT function seen in depressed
patients may themselves result from hypersecretion of cortisol5. Abnormalities of noradrenergic
and dopaminergic neurotransmission are also important in the etiology of depression. Animal
studies suggest norepinephrine plays a major role in maintaining arousal and drive. Although
there is no consistent change in noradrenergic receptor function in patients with depression,
down-regulation of a2 somatodendritic receptors by antidepressant drugs may underlie the
treatment response (Figures 7.12 and 7.13)6. Dopaminergic dysfunction has been reported in
psychotic and bipolar depression, seasonal affective disorder and depression associated with
Parkinson’s disease. Antidepressants may resolve anhedonia and loss of drive by increasing the
sensitization of dopamine D2 and D3 receptors. Manic episodes may be associated with
overactivity in dopamine pathways within the brain, as mania can be provoked by dopamine-
releasing psychostimulants, such as cocaine and amphetamine. Depressed bipolar patients may
be more likely to respond than unipolar patients to dopamine-enhancing agents. such as
bromocriptine or levodopa. Manic episodes occurring after childbirth have been linked to
abnormalities in the release of growth hormone that follows challenge with dopamine-releasing
investigational compounds7.
Low self-esteem, an obsessional personality, the experience of adversity in childhood and
maladaptive negative patterns of thinking about oneself and others, are all recognized
psychologic ‘risk factors’ for depression. Other factors include excessive undesirable recent life
events, usually involving loss (such as bereavement, divorce and redundancy), and persisting
major difficulties, including being a lone parent, overcrowding, prolonged unemployment,
poverty and lack of social support or intimacy.
Psychosocial factors, particularly family dynamics, are undoubtedly important in influencing the
course of bipolar illness once established. However, their role in causing the condition to appear
is unclear. It seems probable that ‘vulnerability’ factors, such as the lack of an intimate confiding
relationship or caring for three or more children under the age of 15 years at home, confer a
predisposition to depression when coupled with threatening life events or chronic social stress.