•
Persistent depression of mood.•
Qualitatively different from normal unhappiness.•
Loss of reactivity to circumstances (‘autonomous’).•
Diurnal rhythm.•
Pervasive.Speech and cognition
•
Decreased tempo and reduction in quantity of speech.•
Guilt, self-blame, worthlessness and hypochondriasis.•
Impaired concentration or slowed thinking, indecisiveness, not associated with incoherence or loosening of associations.•
Suicidal, morbid and paranoid ideation.Somatic/biological/behavioural features
•
Poor appetite, weight loss or, less commonly, increased appetite or significant weight gain.•
Insomnia or hypersomnia – characteristic early morning wakening but also onset of insomnia.•
Psychomotor retardation, agitation – loss of energy and fatigue, decreased libido and loss of interest in pleasure and work activities.‘HYPOMANIC’ AND ‘MANIC’ STATES
Mood•
Persistent elevation of mood.•
Irritability a common feature.•
May be intermingled with transient depression of mood (‘manic’/‘hypomanic’may be used to indicate degree of severity, or presence or absence of delusions and hallucinations).
Speech and cognition
•
Pressure of speech, increased tempo of thinking, impaired concentration and‘flight of ideas’.
•
Distractibility, attention easily drawn to irrelevances.•
Inflated self-image (grandiose, expansive).CLINICAL FEATURES 45
Somatic/biological/behavioural features
•
Increased drive and activity: physical, social, work, libido.•
Excessive activity in risk-taking pursuits, indiscretion socially.•
Insomnia often earliest sign, but no fatigue (EEG shows reduction in delta sleep)•
Appetite good; weight loss is due to overactivity.EPIDEMIOLOGY
Statistics vary widely, depending on diagnostic criteria and ‘caseness’ issues.
Depressive symptoms are very common (13–20 per cent point prevalence).
Results of an epidemiologic catchment area study were:
•
1 month prevalence of 2.2 per cent for major depression.•
Lifetime prevalence of 5.8 per cent for major depression.•
Lifetime prevalence of 0.012 per cent for bipolar disorder.Females are more affected than males. Lifetime prevalence for males is 2.3–4.4 per cent and for females, 4.9–8.7 per cent. Lifetime incidence for males is 10 per cent and for females, 20 per cent.
The lifetime prevalence for bipolar type I is 0.8 per cent. For type II it is 0.5 per cent.
There are no consistent gender differences in rates of bipolar disorder.
Other observations
•
There is concern over increased depression and bipolar illness in young people.•
Onset:– Bipolar disorder most often in mid-20s.
– Unipolar disorder in late 20s.
– Women have peak onset in 30s, males in 40s.
•
There is a higher prevalence of depression in lower social group females (Brown and Harris, 1978).•
Prevalence is higher in urban areas and among the divorced.•
Ethnic differences in the USA appear more related to social class differences.Depression may be becoming more common. From 1910 to 1950 the risk of depres-sion rose in each generation with associated earlier age at onset – the ‘birth cohort effect’.
Unipolar depression was the biggest cause of lifetime disability in the WHO Global Burden of Disease study.
AETIOLOGICAL FACTORS GENETICS
Family studies
High rates of mood disorders have been found in first-degree relatives of bipolar patients – about 20 per cent. The rate of mood disorder in first-degree relatives of unipolar patients is about 10 per cent.
46 AFFECTIVE DISORDERS
Unipolar forms tend to ‘breed true’, but bipolar forms are associated with elevated risk of both unipolar and bipolar disorder in relatives.
Twin studies
•
Unipolar – MZ:DZ⫽ 54%:24%.•
Bipolar – MZ:DZ⫽ 79%:19%.Adoptive studies
Mendlewicz and Rainer (1977) studied relatives of adult bipolar probands who had been adopted early in life and compared them with those of normal adoptees, biological parents of patients with poliomyelitis and bipolar non-adoptees (see Table 4.2).
Molecular genetics
This is a major area of research. For bipolar disorder, genome-wide search reveals evidence of susceptibility genes on chromosomes 4, 12, 13, 18, 21 and 22 (Berrettini, 2001; Liang et al., 2002; Sklar, 2002; Shaw et al., 2003). Chromosomes 13 and 22 are also associated with schizophrenia (see Chapter 3).
For unipolar depression, studies suggest that genetic factors may account for 40–70 per cent of the risk. Genome-wide search reveals susceptibility genes on chromosomes 1, 2, 5, 8, 10, 11, 15, 18, 19 (Zubenko et al., 2003).
NEUROCHEMISTRY
NEUROTRANSMITTER ABNORMALITIES Serotonin
Evidence includes:
•
Decreased:– Plasma tryptophan
– CSF 5-hydroxyindoleacetic acid (5-HIAA) (especially in suicides) – Platelet 5-HT uptake
– 3H-imipramine binding in platelet, in frontal cortex, and in hippocampus – Prolactin response to neuroendocrine challenge tests (intravenous tryptophan,
oral fenfluramine) – responses are then normalized with antidepressant therapy.
•
Increased:– 5-HT2receptor binding in platelets, in cortex of suicides.
AETIOLOGICAL FACTORS 47
Biological Adoptive
Bipolar adoptees 28 12
Bipolar non-adoptees 26 –
Normal controls 5 9
Table 4.2 Percentages of parents affected
Noradrenaline Evidence includes:
•
Decreased:– Growth hormone response to neuroendocrine challenge tests (amphetamine, clonidine, desipramine)
– Platelet CAMP turnover with stimulation by clonidine.
•
Increased:– Platelet ␣2-adrenergic-receptor binding – Beta-adrenergic receptors in suicides.
•
Normal:– CSF, plasma, urinary measures of noradrenaline and MHPG.
Acetylcholine
There is little evidence of abnormality, apart from the cholinergic basis for sleep dis-turbances in affective disorder (see Chapter 14), findings which are consistent with postsynaptic muscarinic supersensitivity.
Dopamine
There have been mixed results in studies of neuroendocrine responses to either apo-morphine or amphetamine.
NEUROENDOCRINE ABNORMALITIES
•
There is blunted growth hormone in response to insulin challenge, and blunted thyroid-stimulating hormone in response to TRH.•
Hypercortisolaemia and loss of normal circadian rhythm of cortisol.•
Failure of cortisol suppression in a dexamethasone suppression test (DST) is seen in 50–60 per cent of depressed patients. Initial optimism that this would be a ‘trait’marker rather than a ‘state’ marker has not held up, and DST non-suppression is seen also in alcoholism, anorexia nervosa, schizophrenia, etc.
Neurochemical and neuroendocrine studies are difficult to assimilate and to detect a consistent pattern for various reasons:
•
There is uncertainty about the origin of metabolites; i.e. does plasma MHPG reflect central noradrenaline metabolism?•
Effects of diet and menstrual status need to be accounted for. Some of these (e.g. appetite) are behavioural features of depression.•
There are varying methodologies, assay techniques, etc.•
There are variable criteria for affective illness and patient selection between studies (e.g. unipolar vs. bipolar).Collectively, the results suggest the overall possibility of:
•
Subsensitivity of noradrenaline postsynaptic receptors•
Presynaptic 5-HT dysfunction.It is most likely that there is an interaction between two or more neurotransmitter systems, perhaps modulated by neuropeptides.
48 AFFECTIVE DISORDERS
NEUROPEPTIDES
The exact role of neuropeptides on mood is unknown. Elevated corticotropin releas-ing factor (CRF) is associated with depression, and CRF neural pathways interact extensively with serotonergic and noradrenergic systems. Administration of CRF in animal studies produces depressive behavior. Research into the effect of CRF receptor antagonists on depression is ongoing.
Antagonists to human substance P (neurokinin 1) receptors were originally developed as a treatment for pain but did not meet with success. However, their efficacy for improving depressive symptoms has been demonstrated in a placebo-controlled trial (Kramer et al., 1998) and further research is under way (Stout et al., 2001).
PSYCHOIMMUNOLOGY
•
There are decreased numbers of natural killer cells, and T-cell replication.•
There is decreased interleukin-2.•
There is increased monocyte activity.Immune deficits are thought to be related to the end-products of sympathetic ner-vous system and hypothalamic–pituitary–adrenal axis activation (i.e. glucocorticoids and catecholamines), which modulate the immune system.
Animal models support the involvement of catecholamine and glucocorticoid lympho-cyte receptors in the immune alterations related to depression (Silberman et al., 2004).